Compositions and methods for inhibition of the jak pathway

ABSTRACT

Disclosed are compounds of formula I, compositions containing them, and methods of use for the compounds and compositions in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK 2 and JAK3, are therapeutically useful.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/692,493, filed Jan. 22, 2010, which claims the benefit of andpriority to U.S. Provisional Application Ser. No. 61/241,630 filed Sep.11, 2009, and U.S. Provisional Application Ser. No. 61/147,059 filedJan. 23, 2009, the contents of which are incorporated herein byreference in their entirety and for all purposes.

INTRODUCTION

1. Field

The present disclosure concerns compounds and methods for their use inmodulation of the JAK pathway, inhibition of one or more JAK kinases andin the treatment of conditions in which modulation of the JAK pathway orinhibition of JAK kinases, particularly JAK3, is therapeutically useful.

2. Background

JAnus Kinases (or JAK) are a family of cytoplasmic protein tyrosinekinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases isselective for the receptors of certain cytokines, though multiple JAKkinases can be affected by particular cytokine or signaling pathways.Studies suggest that JAK3 associates with the common gamma chain (γc) ofthe various cytokine receptors. In particular, JAK3 iselectively bindsto receptors and is part of the cytokine signaling pathway for IL-2,IL-4, IL-7, IL-9, IL-15 and IL-21. The kinase JAK1 interacts with, amongothers, the receptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-21,while JAK2 interacts with, among others, the receptors for IL-9 andTNF-α. Upon the binding of certain cytokines to their receptors (e.g.,IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), receptor oligomerizationoccurs, resulting in the cytoplasmic tails of associated JAK kinasesbeing brought into proximity and facilitating the trans-phosphorylationof tyrosine residues on the JAK kinase. This trans-phosphorylationresults in the activation of the JAK kinase.

Phosphorylated JAK kinases bind various Signal Transducer and Activatorof Transcription (STAT) proteins. These STAT proteins, which are DNAbinding proteins activated by phosphorylation of tyrosine residues,function both as signaling molecules and transcription factors andultimately bind to specific DNA sequences present in the promoters ofcytokine-responsive genes (Leonard et al., (2000), J. Allergy Clin.Immunol. 105:877-888). Signaling of JAK/STAT has been implicated in themediation of many abnormal immune responses such as allergies, asthma,autoimmune diseases such as transplant (allograft) rejection, rheumatoidarthritis, amyotrophic lateral sclerosis and multiple sclerosis, as wellas in solid and hematologic malignancies such as leukemia and lymphomas.For a review of the pharmaceutical intervention of the JAK/STAT pathwaysee Frank, (1999), Mol. Med. 5:432:456 and Seidel et al., (2000),Oncogene 19:2645-2656.

In particular, JAK3 has been implicated in a variety of biologicalprocesses. For example, the proliferation and survival of murine mastcells induced by IL-4 and IL-9 have been shown to be dependent on JAK3-and gamma chain-signaling (Suzuki et al., (2000), Blood 96:2172-2180).Having a crucial role in IgE receptor-mediated mast cell degranulationresponses (Malaviya et al., (1999), Biochem. Biophys. Res. Commun.257:807-813), inhibition of JAK3 kinase has been shown to prevent type Ihypersensitivity reactions, including anaphylaxis (Malaviya et al.,(1999), J. Biol. Chem. 274:27028-27038). JAK3 inhibition has also beenshown to result in immune suppression for allograft rejection (Kirken,(2001), Transpl. Proc. 33:3268-3270). Kinases, particularly JAK3kinases, have also been implicated in the mechanism involved in earlyand late stages of rheumatoid arthritis (Muller-Ladner et al., (2000),J. Immunol. 164:3894-3901); familial amyotrophic lateral sclerosis(Trieu et al., (2000), Biochem Biophys. Res. Commun. 267:22-25);leukemia (Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582);mycosis fungoides, a form of T-cell lymphoma (Nielsen et al., (1997),Prac. Natl. Acad. Sci. USA 94:6764-6769); and abnormal cell growth (Yuet al., (1997), J. Immunol. 159:5206-5210; Catlett-Falcone et al.,(1999), Immunity 10:105-115).

The JAK kinases, including JAK3, are abundantly expressed in primaryleukemic cells from children with acute lymphoblastic leukemia, the mostcommon form of childhood cancer, and studies have correlated STATactivation in certain cells with signals regulating apoptosis (Demoulinet al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997),Blood. 89:4146-52; Kaneko et al., (1997), Clin. Exp. Immun. 109:185-193;and Nakamura et al., (1996), J. Biol. Chem. 271:19483-8). They are alsoknown to be important to lymphocyte differentiation, function andsurvival. In particular, JAK3 plays an essential role in the function oflymphocytes, macrophages, and mast cells. Given the importance of JAKkinases, particularly JAK3, compounds which modulate the JAK pathway,including those selective for JAK3, can be useful for treating diseasesor conditions where the function of lymphocytes, macrophages, or mastcells is involved (Kudlacz et al., (2004) Am. J. Transplant 4:51-57;Changelian (2003) Science 302:875-878). Conditions in which targeting ofthe JAK pathway or modulation of the JAK kinases, particularly JAK3, arecontemplated to be therapeutically useful include, leukemia, lymphoma,transplant rejection (e.g., pancreas islet transplant rejection, bonemarrow transplant applications (e.g., graft-versus-host disease),autoimmune diseases (e.g., diabetes), and inflammation (e.g., asthma,allergic reactions). Conditions which can benefit for inhibition of JAK3are discussed in greater detail below.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of the JAK pathway it is immediatelyapparent that new compounds that modulate JAK pathways and methods ofusing these compounds should provide substantial therapeutic benefits toa wide variety of patients. Provided herein are novel2,4-pyrimidinediamine compounds for use in the treatment of conditionsin which targeting of the JAK pathway or inhibition of JAK kinases,particularly JAK3, are therapeutically useful.

SUMMARY

In one embodiment, the present disclosure is directed to compounds,prodrugs, and methods of using these compounds and prodrugs thereof inthe treatment of conditions in which modulation of the JAK pathway orinhibition of JAK kinases, particularly JAK2, JAK3, or both, will betherapeutically useful.

One embodiment, disclosed herein includes a compound of formula I, asalt thereof, or a pharmaceutical composition including the compound:

where:

-   -   X and Y are each independently O, S, S(O), SO₂ or NR¹;    -   each R¹ is independently for each occurrence H, optionally        substituted C₁₋₆alkyl, C(O)—C₁₋₆alkyl, CO₂—C₁₋₆alkyl or R⁵⁰;    -   each R⁵⁰ is —C(R⁹)₂-A-R¹⁰, where A is O or S; each R⁹ is        independently for each occurrence H, optionally substituted        C₁₋₆alkyl, optionally substituted C₆₋₁₀aryl or optionally        substituted C₇₋₁₆arylalkyl; or alternatively, two R⁹, together        with the carbon to which they are attached, form an optionally        substituted C₃₋₈cycloalkyl group or an optionally substituted        3-8 membered heteroalicyclyl; R¹⁰ is R^(a) or —P(O)(OR¹¹)₂; each        R¹¹ is independently for each occurrence R^(a) or a monovalent        cationic group; or two R¹¹, together with the atoms to which        they are attached, form a 4-8 membered cyclic phosphate group,        or two R¹¹ together represent a divalent cationic group;    -   ring A is a C₆₋₁₀aryl or a 5-10 membered heteroaryl;    -   each R² is independently for each occurrence H, R^(e), R^(b),        R^(e) substituted with one or more of the same or different        R^(a) and/or R^(b), —OR^(e) substituted with one or more of the        same or different R^(a) and/or R^(b), —SR^(e) substituted with        one or more of the same or different R^(a) and/or R^(b),        —C(O)R^(e) substituted with one or more of the same or different        R^(a) and/or R^(b), —N(R^(a))R^(e) where R^(e) is substituted        with one or more of the same or different R^(a) and/or R^(b),        —S(O)₂R^(e) substituted with one or more of the same or        different R^(a) and/or R^(b), —N(R^(a))—S(O)₂R^(e) where R^(e)        is substituted with one or more of the same or different R^(a)        and/or R^(b), —B(OR^(a))₂, —B(N(R^(c))₂)₂,        —(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(a))₂)_(m)—R^(b),        —S—(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(b))₂)_(m)—R^(a),        —N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),        —C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —O—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N((C(R^(a))₂)_(m)R^(b))₂,        —S—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)R^(b),        —N(R^(a))—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N(R^(a))—C(O)—(C(R^(a))₂)_(m)—C(R^(a))(R^(b))₂ or        —N(R^(a))—(C(R^(a))₂)_(m)—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b);    -   each R^(a) is independently for each occurrence H, deuterium,        C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,        C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-10 membered        heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15        membered heteroaryl or 6-16 membered heteroarylalkyl;    -   each R^(b) is independently for each occurrence ═O, —OR^(a),        —O—(C(R^(a))₂)_(m)—OR^(a), haloC₁₋₃alkyloxy, ═S, —SR^(a),        ═NR^(a), ═NOR^(a), —N(R^(c))₂, halo, —CF₃, —CN, —NC, —OCN, —SCN,        —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O)₂R^(a), —SO₃R^(a),        —S(O)N(R^(c))₂, —S(O)₂N(R^(c))₂, —OS(O)R^(a), —OS(O)₂R^(a),        —OSO₃R^(a), —OS(O)₂N(R^(c))₂, —C(O)R^(a), —CO₂R^(a),        —C(O)N(R^(c))₂, —C(NR^(a))—N(R^(c))₂, —C(NOH)—R^(a),        —C(NOH)—N(R^(c))₂, —OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(c))₂,        —OC(NH)—N(R^(c))₂, —OC(NR^(a))—N(R^(c))₂, —N(R^(a))—S(O)₂H,        —[N(R^(a))C(O)]_(n)R^(a), —[N(R^(a))C(O)]OR^(a),        —[N(R^(a))C(O)]_(n)N(R^(c))₂ or        —[N(R^(a))C(NR^(a))]_(n)—N(R^(c))₂;    -   each R^(c) is independently for each occurrence R^(a), or,        alternatively, two R^(c) are taken together with the nitrogen        atom to which they are bonded to form a 3 to 10-membered        heteroalicyclyl or a 5-10 membered heteroaryl which may        optionally include one or more of the same or different        additional heteroatoms and which is optionally substituted with        one or more of the same or different R^(a) and/or R^(d) groups;    -   each R^(d) is ═O, —OR^(a), haloC₁₋₃alkyloxy, C₁₋₆alkyl, ═S,        —SR^(a), ═NR^(a), ═NOR^(a), —N(R^(a))₂, halo, —CF₃, —CN, —NC,        —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O₂)R^(a),        —SO₃R^(a), —S(O)N(R^(a))₂, —S(O)₂N(R^(a))₂, —OS(O)R^(a),        —OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(a))₂, —C(O)R^(a),        —CO₂R^(a), —C(O)N(R^(a))₂, —C(NR^(a))N(R^(a))₂, —C(NOH)R^(a),        —C(NOH)N(R^(a))₂, —OCO₂R^(a), —OC(O)N(R^(a))₂,        —OC(NR^(a))N(R^(a))₂, —[N(R^(a))C(O)]_(n)R^(a),        —(C(R^(a))₂)_(n)—OR^(a), —N(R^(a))—S(O)₂R^(a),        —C(O)—C₁₋₆haloalkyl, —S(O)₂C₁₋₆haloalkyl, —OC(O)R^(a),        —O(C(R^(a))₂)_(m)—OR^(a), —S(C(R^(a))₂)_(m)—OR^(a),        —N(R^(a))C₁₋₆haloalkyl, —P(O)(OR^(a))₂,        —N(R^(a))—(C(R^(a))₂)_(m)—OR^(a), —[N(R^(a))C(O)]_(n)OR^(a),        —[N(R^(a))C(O)]_(n)N(R^(a))₂, —[N(R^(a))C(NR^(a))]_(n)N(R^(a))₂        or —N(R^(a))C(O)C₁₋₆haloalkyl; two R^(d), taken together with        the atom or atoms to which they are attached, combine to form a        3-10 membered partially or fully saturated mono or bicyclic        ring, optionally containing one or more heteroatoms and        optionally substituted with one or more R^(a);    -   each R^(e) is independently for each occurrence C₁₋₆alkyl,        C₃₋₈cycloalkyl, C₄₋₁₁ cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆        arylalkyl, 2-6 membered heteroalkyl, 3-10 membered        heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15        membered heteroaryl or 6-16 membered heteroarylalkyl;    -   p is 0, 1, 2, 3 or 4;    -   each m is 1, 2 or 3;    -   each n is 0, 1, 2 or 3;    -   two R² groups, taken together with the atom or atoms to which        they are attached, combine to form a 4-10 membered partially or        fully saturated mono or bicyclic ring, optionally containing one        or more heteroatoms and optionally substituted with one or more        R^(a) and/or R^(b);    -   Z¹ and Z² are each independently CH, CR² or N;    -   R³ is H, optionally substituted C₁₋₆alkyl or R⁵⁰;    -   R⁴ is H, optionally substituted C₁₋₆alkyl or R⁵⁰; and    -   R⁵ is halo, —CN, optionally substituted C₁₋₆alkyl, alkynyl,        hydroxy, optionally substituted C₁₋₆alkoxy, nitro, —N(R^(a))₂,        —C(O)N(R^(a))₂, —CO₂R^(a) or —C(O)R^(a).

Another embodiment is a method of inhibiting an activity of a JAKkinase, including contacting the JAK kinase with an amount of a compoundeffective to inhibit an activity of the JAK kinase where the compound isaccording to formula I as described herein. In one embodiment thecontact is made in vitro, in another embodiment the contact is made invivo.

Another embodiment is a method of treating a T-cell mediated autoimmunedisease, including administering to a patient suffering from such anautoimmune disease an amount of a compound effective to treat theautoimmune disease where the compound is according to formula I asdescribed herein.

Another embodiment is a method of treating allograft transplantrejection in a transplant recipient, including administering to thetransplant recipient an amount of a compound effective to treat orprevent the rejection where the compound is according to formula I asdescribed herein. Administration in this context may include contactinga transplant organ with a compound or pharmaceutical compositiondescribed herein prior to transplant and/or concurrent withadministration to the transplant recipient.

Yet another embodiment is a method of treating a Type IVhypersensitivity reaction, including administering to a subject anamount of a compound of effective to treat or prevent thehypersensitivity reaction where the compound is according to formula Ias described herein.

Another embodiment is a method of treating an ocular disease ordisorder, including administering to a subject an amount of a compoundof effective to treat or prevent the ocular disease or disorder wherethe compound is according to formula I as described herein.

Another embodiment is a method of inhibiting a signal transductioncascade in which JAK3 kinase plays a role, including contacting a cellexpressing a receptor involved in such a signaling cascade with acompound where the compound is according to formula I as describedherein.

Another embodiment is a method of treating a JAK kinase-mediateddisease, including administering to a subject an amount of compoundeffective to treat or prevent the JAK kinase-mediated disease where thecompound is according to formula I as described herein.

Another embodiment is a pharmaceutical formulation including a compoundof formula I as described herein. Therapy using the2,4-pyrimidinediamine compounds and pharmaceutical formulationsdescribed herein can be applied alone, or it can be applied incombination with or adjunctive to other immunosuppressive therapies

Another embodiment is a kit including a compound of formula I asdescribed herein, a prodrug thereof or pharmaceutical compositionincluding a compound thereof, packaging and instructions for use.

Another embodiment is a unit dosage formulation including a compound offormula I as described herein, a prodrug thereof or pharmaceuticalcomposition including a compound of formula I.

Other embodiments include methods of using the compounds for screeningfor other agents used to treat or prevent a JAK kinase mediated disease.

More detailed description for these and other embodiments is providedbelow.

DETAILED DESCRIPTION Overview

The invention encompasses compounds of formula I and the compositionsand methods using these compounds in the treatment of conditions inwhich modulation of the JAK pathway or inhibition of JAK kinases,particularly JAK3, are therapeutically useful. Formulations, uses asscreening agents and other utilities are also described.

Terms

As used herein, the following words and phrases are intended to have themeanings as set forth below, except to the extent that the context inwhich they are used indicates otherwise or they are expressly defined tomean something different.

The symbol “

” means a single bond, “

” means a double bond, “

” means a triple bond. The symbol “

” refers to a group on a double-bond as occupying either position on theterminus of the double bond to which the symbol is attached; that is,the geometry, E- or Z-, of the double bond is ambiguous and both isomersare meant to be included. When a group is depicted removed from itsparent formula, the “

” symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It would be understood by one of ordinary skillin the art that the aforementioned descriptive techniques are common inthe chemical arts to provide brevity and simplicity to description ofotherwise complex structures.

In this application, some ring structures are depicted generically andwill be described textually. For example, in the schematic below if ringA is used to describe a phenyl, there are at most four hydrogens on ringA (when R is not H).

If a group R is depicted as “floating” on a ring system, as for examplein the group:

then, unless otherwise defined, a substituent R can reside on any atomof the fused bicyclic ring system, excluding the atom carrying the bondwith the “

” symbol, so long as a stable structure is formed. In the exampledepicted, the R group can reside on an atom in either the 5-membered orthe 6-membered ring of the indolyl ring system.

When there are more than one such depicted “floating” groups, as forexample in the formulae:

where there are two groups, namely, the R and the bond indicatingattachment to a parent structure; then, unless otherwise defined, the“floating” groups can reside on any atoms of the ring system, againassuming each replaces a depicted, implied, or expressly definedhydrogen on the ring system and a chemically stable compound would beformed by such an arrangement.

When a group R is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, y can be more than one, assuming each replaces acurrently depicted, implied, or expressly defined hydrogen on the ring;then, unless otherwise defined, two R's can reside on the same carbon. Asimple example is when R is a methyl group; there can exist a geminaldimethyl on a carbon of the depicted ring (an “annular” carbon). Inanother example, two R's on the same carbon, including that same carbon,can form a ring, thus creating a spirocyclic ring (a “spirocyclyl”group) structure. Using the previous example, where two R's form, e.g. apiperidine ring in a spirocyclic arrangement with the cyclohexane, asfor example in the formula:

“Alkyl” in its broadest sense is intended to include linear, branched,or cyclic hydrocarbon structures, and combinations thereof. Alkyl groupscan be fully saturated or with one or more units of unsaturation, butnot aromatic. Generally alkyl groups are defined by a subscript, eithera fixed integer or a range of integers. For example, “C₈alkyl” includesn-octyl, iso-octyl, 3-octynyl, cyclohexenylethyl, cyclohexylethyl, andthe like; where the subscript “8” designates that all groups defined bythis term have a fixed carbon number of eight. In another example, theterm “C₁₋₆alkyl” refers to alkyl groups having from one to six carbonatoms and, depending on any unsaturation, branches and/or rings, therequisite number of hydrogens. Examples of C₁₋₆alkyl groups includemethyl, ethyl, vinyl, propyl, isopropyl, butyl, s-butyl, t-butyl,isobutyl, isobutenyl, pentyl, pentynyl, hexyl, cyclohexyl, hexenyl, andthe like. When an alkyl residue having a specific number of carbons isnamed generically, all geometric isomers having that number of carbonsare intended to be encompassed. For example, either “propyl” or“C₃alkyl” each include n-propyl, c-propyl, propenyl, propynyl, andisopropyl. Cycloalkyl is a subset of alkyl and includes cyclichydrocarbon groups of from three to thirteen carbon atoms. Examples ofcycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl,norbornenyl, c-hexenyl, adamantyl and the like. As mentioned, alkylrefers to alkanyl, alkenyl, and alkynyl residues (and combinationsthereof)—it is intended to include, e.g., cyclohexylmethyl, vinyl,allyl, isoprenyl, and the like. An alkyl with a particular number ofcarbons can be named using a more specific but still generic geometricalconstraint, e.g. “C₃₋₆cycloalkyl” which means only cycloalkyls havingbetween 3 and 6 carbons are meant to be included in that particulardefinition. Unless specified otherwise, alkyl groups, whether alone orpart of another group, e.g. —C(O)alkyl, have from one to twenty carbons,that is C₁₋₂₀alkyl. In the example “—C(O)alkyl,” where there were nocarbon count limitations defined, the carbonyl of the —C(O)alkyl groupis not included in the carbon count, since “alkyl” is designatedgenerically. But where a specific carbon limitation is given, e.g. inthe term “optionally substituted C₁₋₂₀alkyl,” where the optionalsubstitution includes “oxo” the carbon of any carbonyls formed by such“oxo” substitution are included in the carbon count since they were partof the original carbon count limitation. However, again referring to“optionally substituted C₁₋₂₀alkyl,” if optional substitution includescarbon-containing groups, e.g. —CH₂CO₂H, the two carbons in this groupare not included in the C₁₋₂₀alkyl carbon limitation.

When a carbon number limit is given at the beginning of a term whichitself comprises two terms, the carbon number limitation is understoodas inclusive for both terms. For example, for the term “C₇₋₁₄arylalkyl,”both the “aryl” and the “alkyl” portions of the term are included thecarbon count, a maximum of 14 in this example, but additionalsubstituent groups thereon are not included in the atom count unlessthey incorporate a carbon from the group's designated carbon count, asin the “oxo” example above. Likewise when an atom number limit is given,for example “6-14 membered heteroarylalkyl,” both the “heteroaryl” andthe “alkyl” portion are included the atom count limitation, butadditional substituent groups thereon are not included in the atom countunless they incorporate a carbon from the group's designated carboncount. In another example, “C₄₋₁₀cycloalkylalkyl” means a cycloalkylbonded to the parent structure via an alkylene, alkylidene oralkylidyne; in this example the group is limited to 10 carbons inclusiveof the alkylene, alkylidene or alkylidyne subunit. As another example,the “alkyl” portion of, e.g. “C₇₋₁₄arylalkyl” is meant to includealkylene, alkylidene or alkylidyne, unless stated otherwise, e.g. as inthe terms “C₇₋₁₄arylalkylene” or “C₆₋₁₀aryl-CH₂CH₂—.”

“Alkylene” refers to straight, branched and cyclic (and combinationsthereof) divalent radical consisting solely of carbon and hydrogenatoms, containing no unsaturation and having from one to ten carbonatoms, for example, methylene, ethylene, propylene, n-butylene and thelike. Alkylene is like alkyl, referring to the same residues as alkyl,but having two points of attachment and, specifically, fully saturated.Examples of alkylene include ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), dimethylpropylene (—CH₂C(CH₃)₂CH₂—), cyclohexan-1,4-diyland the like.

“Alkylidene” refers to straight, branched and cyclic (and combinationsthereof) unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from two to ten carbon atoms, for example,ethylidene, propylidene, n-butylidene, and the like. Alkylidene is likealkyl, referring to the same residues as alkyl, but having two points ofattachment and, specifically, at least one unit of double bondunsaturation. Examples of alkylidene include vinylidene (—CH═CH—),cyclohexylvinylidene (—CH═C(C₆H₁₃)—), cyclohexen-1,4-diyl and the like.

“Alkylidyne” refers to straight, branched and cyclic (and combinationsthereof) unsaturated divalent radical consisting solely of carbon andhydrogen atoms having from two to ten carbon atoms, for example,propylid-2-ynyl, n-butylid-1-ynyl, and the like. Alkylidyne is likealkyl, referring to the same residues as alkyl, but having two points ofattachment and, specifically, at least one unit of triple bondunsaturation.

Any of the above radicals” “alkylene,” “alkylidene” and “alkylidyne,”when optionally substituted, can contain alkyl substitution which itselfcan contain unsaturation. For example,2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains ann-butylid-3-ynyl radical with a vinyl substituent at the 2-position ofthe radical. Combinations of alkyls and carbon-containing substitutionsthereon are limited to thirty carbon atoms.

“Alkoxy” refers to the group —O-alkyl, where alkyl is as defined herein.Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, cyclohexyloxy,cyclohexenyloxy, cyclopropylmethyloxy, and the like.

“Haloalkyloxy” refers to the group —O-alkyl, where alkyl is as definedherein, and further, alkyl is substituted with one or more halogens. Byway of example, a haloC₁₋₃alkyloxy″ group includes —OCF₃, —OCF₂H,—OCHF₂, —OCH₂CH₂Br, —OCH₂CH₂CH₂I, —OC(CH₃)₂Br, —OCH₂Cl and the like.

“Acyl” refers to the groups —C(O)H, —C(O)alkyl, —C(O)aryl and—C(O)heterocyclyl.

“α-Amino Acids” refer to naturally occurring and commercially availableα-amino acids and optical isomers thereof. Typical natural andcommercially available α-amino acids are glycine, alanine, serine,homoserine, threonine, valine, norvaline, leucine, isoleucine,norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine,arginine, cysteine, homocysteine, methionine, phenylalanine,homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine,para-tyrosine, tryptophan, glutamine, asparagine, proline andhydroxyproline. A “side chain of an α-amino acid” refers to the radicalfound on the α-carbon of an α-amino acid as defined above, for example,hydrogen (for glycine), methyl (for alanine), benzyl (forphenylalanine), etc.

“Amino” refers to the group —NH₂.

“Amide” refers to the group —C(O)NH₂ or —N(H)acyl.

“Aryl” (sometimes referred to as “Ar”) refers to a monovalent aromaticcarbocyclic group of, unless specified otherwise, from 6 to 15 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl) which condensed rings may or may not bearomatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl,9,10-dihydrophenanthrenyl, indanyl, tetralinyl, and fluorenyl and thelike), provided that the point of attachment is through an atom of anaromatic portion of the aryl group and the aromatic portion at the pointof attachment contains only carbons in the aromatic ring. If anyaromatic ring portion contains a heteroatom, the group is a heteroaryland not an aryl. Aryl groups are monocyclic, bicyclic, tricyclic ortetracyclic.

“Arylene” refers to an aryl that has at least two groups attachedthereto. For a more specific example, “phenylene” refers to a divalentphenyl ring radical. A phenylene, thus can have more than two groupsattached, but is defined by a minimum of two non-hydrogen groupsattached thereto.

“Arylalkyl” refers to a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidyneradical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyland the like. When specified as “optionally substituted,” both the aryl,and the corresponding alkylene, alkylidene, or alkylidyne portion of anarylalkyl group can be optionally substituted. By way of example, “C₇₋₁₁arylalkyl” refers to an arylalkyl limited to a total of eleven carbons,e.g., a phenylethyl, a phenylvinyl, a phenylpentyl and a naphthylmethylare all examples of a “C₇₋₁₁arylalkyl” group.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein,including, by way of example, phenoxy, naphthoxy, and the like.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H or salts thereof.

“Carboxyl ester” or “carboxy ester” or “ester” refers to the group—CO₂alkyl, —CO₂aryl or —CO₂heterocyclyl.

“Carbonate” refers to the group —OCO₂alkyl, —OCO₂aryl or—OCO₂heterocyclyl.

“Carbamate” refers to the group —OC(O)NH₂, —N(H)carboxyl or—N(H)carboxyl ester.

“Cyano” or “nitrile” refers to the group —CN.

“Formyl” refers to the specific acyl group —C(O)H.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” and “haloaryl” refer generically to alkyl and aryl radicalsthat are substituted with one or more halogens, respectively. By way ofexample “dihaloaryl,” “dihaloalkyl,” “trihaloaryl” etc. refer to aryland alkyl substituted with a plurality of halogens, but not necessarilya plurality of the same halogen; thus 4-chloro-3-fluorophenyl is adihaloaryl group.

“Heteroalkyl” refers to an alkyl where one or more, but not all, carbonsare replaced with a heteroatom. A heteroalkyl group has either linear orbranched geometry. By way of example, a “2-6 membered heteroalkyl” is agroup that can contain no more than 5 carbon atoms, because at least oneof the maximum 6 atoms must be a heteroatom, and the group is linear orbranched. Also, for the purposes of this invention, a heteroalkyl groupalways starts with a carbon atom, that is, although a heteroalkyl maycontain one or more heteroatoms, the point of attachment to the parentmolecule is not a heteroatom. A 2-6 membered heteroalkyl group includes,for example, —CH₂XCH₃, —CH₂CH₂XCH₃, —CH₂CH₂XCH₂CH₃, —C(CH₂)₂XCH₂CH₃ andthe like, where X is O, NH, NC₁₋₆alkyl and S(O)₀₋₂, for example.

“Perhalo” as a modifier means that the group so modified has all itsavailable hydrogens replaced with halogens. An example would be“perhaloalkyl.” Perhaloalkyls include —CF₃, —CF₂CF₃, perchloroethyl andthe like.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” in the broadest sense includes aromatic and non-aromaticring systems and more specifically refers to a stable three- tofifteen-membered ring radical that consists of carbon atoms and from oneto five heteroatoms. For purposes of this invention, the heterocyclylradical can be a monocyclic, bicyclic or tricyclic ring system, whichcan include fused or bridged ring systems as well as spirocyclicsystems; and the nitrogen, phosphorus, carbon or sulfur atoms in theheterocyclyl radical can be optionally oxidized to various oxidationstates. In a specific example, the group —S(O)₀₋₂—, refers to —S—(sulfide), —S(O)— (sulfoxide), and —SO₂— (sulfone) linkages. Forconvenience, nitrogens, particularly but not exclusively, those definedas annular aromatic nitrogens, are meant to include their correspondingN-oxide form, although not explicitly defined as such in a particularexample. Thus, for a compound having, for example, a pyridyl ring; thecorresponding pyridyl-N-oxide is meant to be included in the presentlydisclosed compounds. In addition, annular nitrogen atoms can beoptionally quaternized. “Heterocycle” includes heteroaryl andheteroalicyclyl, that is a heterocyclic ring can be partially or fullysaturated or aromatic. Thus a term such as “heterocyclylalkyl” includesheteroalicyclylalkyls and heteroarylalkyls. Examples of heterocyclylradicals include, but are not limited to, azetidinyl, acridinyl,benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl,dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Heteroaryl” refers to an aromatic group having from 1 to 10 annularcarbon atoms and 1 to 4 annular heteroatoms. Heteroaryl groups have atleast one aromatic ring component, but heteroaryls can be fullyunsaturated or partially unsaturated. If any aromatic ring in the grouphas a heteroatom, then the group is a heteroaryl, even, for example, ifother aromatic rings in the group have no heteroatoms. For example,2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-7-yl, indolyl and benzimidazolylare “heteroaryls.” Heteroaryl groups can have a single ring (e.g.,pyridinyl, imidazolyl or furyl) or multiple condensed rings (e.g.,indolizinyl, quinolinyl, benzimidazolyl or benzothienyl), where thecondensed rings may or may not be aromatic and/or contain a heteroatom,provided that the point of attachment to the parent molecule is throughan atom of the aromatic portion of the heteroaryl group. In oneembodiment, the nitrogen and/or sulfur ring atom(s) of the heteroarylgroup are optionally oxidized to provide for the N-oxide (N→O),sulfinyl, or sulfonyl moieties. Compounds described herein containingphosphorous, in a heterocyclic ring or not, include the oxidized formsof phosphorous. Heteroaryl groups are monocyclic, bicyclic, tricyclic ortetracyclic.

“Heteroaryloxy” refers to —O-heteroaryl.

“Heteroarylene” generically refers to any heteroaryl that has at leasttwo groups attached thereto. For a more specific example, “pyridylene”refers to a divalent pyridyl ring radical. A pyridylene, thus can havemore than two groups attached, but is defined by a minimum of twonon-hydrogen groups attached thereto.

“Heteroalicyclic” refers specifically to a non-aromatic heterocyclylradical. A heteroalicyclic may contain unsaturation, but is notaromatic. As mentioned, aryls and heteroaryls are attached to the parentstructure via an aromatic ring. So, e.g.,2H-1,4-benzoxazin-3(4H)-one-4-yl is a heteroalicyclic, while2H-1,4-benzoxazin-3(4H)-one-7-yl is an aryl. In another example,2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-4-yl is a heteroalicyclic, while2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-7-yl is a heteroaryl.

“Heterocyclylalkyl” refers to a heterocyclyl group linked to the parentstructure via e.g. an alkylene linker, for example(tetrahydrofuran-3-yl)methyl- or (pyridin-4-yl)methyl

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Nitro” refers to the group —NO₂.

“Oxo” refers to a double bond oxygen radical, ═O.

“Oxy” refers to —O. radical (also designated as

O), that is, a single bond oxygen radical. By way of example, N-oxidesare nitrogens bearing an oxy radical.

When a group with its bonding structure is denoted as being bonded totwo partners; that is, a divalent radical, for example, —OCH₂—, then itis understood that either of the two partners can be bound to theparticular group at one end, and the other partner is necessarily boundto the other end of the divalent group, unless stated explicitlyotherwise. Stated another way, divalent radicals are not to be construedas limited to the depicted orientation, for example “—OCH₂—” is meant tomean not only “—OCH₂—” as drawn, but also “—CH₂O—.”

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that,with respect to any molecule described as containing one or moreoptional substituents, that only synthetically feasible compounds aremeant to be included. “Optionally substituted” refers to all subsequentmodifiers in a term, for example in the term “optionally substitutedarylC₁₋₈alkyl,” optional substitution may occur on both the “C₁₋₈alkyl”portion and the “aryl” portion of the arylC₁₋₈alkyl group. Also by wayof example, optionally substituted alkyl includes optionally substitutedcycloalkyl groups. The term “substituted,” when used to modify aspecified group or radical, means that one or more hydrogen atoms of thespecified group or radical are each, independently of one another,replaced with the same or different substituent groups as defined below.Thus, when a group is defined as “optionally substituted” the definitionis meant to encompass when the groups is substituted with one or more ofthe radicals defined below, and when it is not so substituted.

Substituent groups for substituting for one or more hydrogens (any twohydrogens on a single carbon can be replaced with ═O, ═NR⁷⁰, ═N—OR⁷⁰,═N₂ or ═S) on saturated carbon atoms in the specified group or radicalare, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰, —N(R⁸⁰)₂,perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(O⁻)₂M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ is C₁₋₆alkyl, 3 to10-membered heterocyclyl, 3 to 10-membered heterocyclylC₁₋₆alkyl,C₆₋₁₀aryl or C₆₋₁₀arylC₁₋₆alkyl; each R⁷⁰ is independently for eachoccurrence hydrogen or R⁶⁰; each R⁸⁰ is independently for eachoccurrence R⁷⁰ or alternatively, two R⁸⁰'s, taken together with thenitrogen atom to which they are bonded, form a 3 to 7-memberedheteroalicyclyl which optionally includes from 1 to 4 of the same ordifferent additional heteroatoms selected from O, N and S, of which Noptionally has H or C₁-C₃alkyl substitution; and each M⁺ is a counterion with a net single positive charge. Each M⁺ is independently for eachoccurrence, for example, an alkali ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as ⁺N(R⁶⁰)₄; or an alkaline earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (a “subscript 0.5 means e.g.that one of the counter ions for such divalent alkali earth ions can bean ionized form of a compound of the invention and the other a typicalcounter ion such as chloride, or two ionized compounds can serve ascounter ions for such divalent alkali earth ions, or a doubly ionizedcompound can serve as the counter ion for such divalent alkali earthions). As specific examples, —N(R⁸⁰)₂ is meant to include —NH₂,—NH-alkyl, —NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like.

Substituent groups for replacing hydrogens on unsaturated carbon atomsin groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂,perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined, provided that in case of substituted alkene oralkyne, the substituents are not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogens on nitrogen atoms in groupscontaining such nitrogen atoms are, unless otherwise specified, —R⁶⁰,—O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —NO, —NO₂,—S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃²⁻(M⁺)₂, —PO₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In one embodiment, a group that is substituted has 1, 2, 3, or 4substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1substituent.

It is understood that in all substituted groups, polymers arrived at bydefining substituents with further substituents to themselves (e.g.,substituted aryl having a substituted aryl group as a substituent whichis itself substituted with a substituted aryl group, which is furthersubstituted by a substituted aryl group, etc.) are not intended forinclusion herein. In such case that the language permits such multiplesubstitutions, the maximum number of such iterations of substitution isthree.

“Sulfonamide” refers to the group —SO₂NH₂, —N(H)SO₂H, —N(H)SO₂alkyl,—N(H)SO₂aryl, or —N(H)SO₂heterocyclyl.

“Sulfonyl” refers to the group —SO₂H, —SO₂alkyl, —SO₂aryl, or—SO₂heterocyclyl.

“Sulfanyl” refers to the group: —SH, —S-alkyl, —S-aryl, or—S-heterocyclyl.

“Sulfinyl” refers to the group: —S(O)H, —S(O)alkyl, —S(O)aryl or—S(O)heterocyclyl.

“Suitable leaving group” is defined as the term would be understood byone of ordinary skill in the art; that is, a group on a carbon, whereupon reaction a new bond is to be formed, the carbon loses the groupupon formation of the new bond. A typical example employing a suitableleaving group is a nucleophilic substitution reaction, e.g., on a sp^(a)hybridized carbon (SN₂ or SN₁), e.g. where the leaving group is ahalide, such as a bromide, the reactant might be benzyl bromide. Anothertypical example of such a reaction is a nucleophilic aromaticsubstitution reaction (SNAr). Another example is an insertion reaction(for example by a transition metal) into the bond between an aromaticreaction partner bearing a leaving group followed by reductive coupling.“Suitable leaving group” is not limited to such mechanisticrestrictions. Examples of suitable leaving groups include halogens,optionally substituted aryl or alkyl sulfonates, phosphonates, azidesand —S(O)₀₋₂R where R is, for example optionally substituted alkyl,optionally substituted aryl, or optionally substituted heteroaryl. Thoseof skill in the art of organic synthesis will readily identify suitableleaving groups to perform a desired reaction under different reaction.

“Stereoisomer” and “stereoisomers” refer to compounds that have the sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomersand diastereomers. Compounds of the invention, or their pharmaceuticallyacceptable salts can contain one or more asymmetric centers and can thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat can be defined, in terms of absolute stereochemistry, as (R)- or(S)- or, as (D)- or (L)- for amino acids. The present invention is meantto include all such possible isomers, as well as their racemic andoptically pure forms. Optically active (+) and (−), (R)- and (S)-, or(D)- and (L)-isomers can be prepared using chiral synthons, chiralreagents, or resolved using conventional techniques, such as by:formation of diastereoisomeric salts or complexes which can beseparated, for example, by crystallization; via formation ofdiastereoisomeric derivatives which can be separated, for example, bycrystallization, selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer can be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer can be further enriched (withconcomitant loss in yield) by recrystallization.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.

“Tautomer” refers to alternate forms of a molecule that differ only inelectronic bonding of atoms and/or in the position of a proton, such asenol-keto and imine-enamine tautomers, or the tautomeric forms ofheteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, suchas pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Aperson of ordinary skill in the art would recognize that othertautomeric ring atom arrangements are possible and contemplated herein.

“Para” for the purposes of this invention refers to the position of asubstituent on a phenyl or a six-membered heteroaryl ring relative toanother substituent on the ring; the relative position being1,4-substitution. That is, starting from one substituent as beingattached to a first atom of the six-membered ring and, counting atomsinclusive of the first atom, another substituent is on atom 4 of thesix-membered ring, the substituents' relative orientation about thesix-membered ring is “para.” For example compound L, depicted below, hasa methyl group “para” to N2 of the pyrimidinediamine; compound M alsohas a “para” methyl group.

“Patient” or “Subject” refers to mammals and other animals, particularlyhumans. Thus the methods are applicable to both human therapy andveterinary applications. In one embodiment the patient or subject is amammal. In another embodiment the patient or subject is a human.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound, which salts are derived from a variety of organicand inorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate, and the like. Pharmaceutically acceptable acid addition saltsare those salts that retain the biological effectiveness of the freebases while formed by acid partners that are not biologically orotherwise undesirable, e.g., inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, as well as organic acids such as acetic acid, trifluoroaceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike. Pharmaceutically acceptable base addition salts include thosederived from inorganic bases such as sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Exemplary salts are the ammonium, potassium, sodium,calcium, and magnesium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include, but are not limited to,salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.(See, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977; 66:1-19 which is incorporated herein by reference.)

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder. The amount of a compound whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the disease state and its severity, the age of the patientto be treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art.

“Prodrug” refers to compounds that are transformed in vivo to yield theparent compound, for example, by hydrolysis in the gut or enzymaticconversion in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)where the alkyl group is a straight or branched chain. Acceptable estersalso include cycloalkyl esters and arylalkyl esters such as, but notlimited to benzyl. Examples of pharmaceutically acceptable amides of thecompounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention can be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8^(th)Ed., Pergamon Press, Gilman et al. (eds), 1990 which is hereinincorporated by reference). The metabolite of a compound describedherein or its salt can itself be a biologically active compound in thebody. While a prodrug described herein would meet this criteria, thatis, form a described biologically active parent compound in vivo,“metabolite” is meant to encompass those compounds not contemplated tohave lost a progroup, but rather all other compounds that are formed invivo upon administration of a compound of the invention which retain thebiological activities described herein. Thus one aspect disclosed2,4-pyrimidine diamine compounds specifically contemplated herein is ametabolite of a compound described herein. For example, a biologicallyactive metabolite is discovered serendipitously, that is, no prodrugdesign per se was undertaken. Stated another way, biologically activecompounds inherently formed as a result of practicing methods of theinvention, are contemplated and disclosed herein. “Solvate” refers to acomplex formed by combination of solvent molecules with molecules orions of the solute. The solvent can be an organic compound, an inorganiccompound, or a mixture of both. Some examples of solvents include, butare not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran,dimethylsulfoxide, and water. The compounds described herein can existin unsolvated as well as solvated forms with solvents, pharmaceuticallyacceptable or not, such as water, ethanol, and the like. Solvated formsof the presently disclosed compounds are contemplated herein and areencompassed by the invention, at least in generic terms.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingregression of the disease or condition or a symptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns areeasily recognized by a person having ordinary skill in the art.

Compounds and Compositions

Disclosed herein are novel 2,4-pyrimidinediamine compounds, prodrugs ofthe compounds, methods of making the compounds, and methods of usingthese compounds in the treatment of conditions in which targeting of theJAK pathway or modulation, including inhibition, of JAK kinases,particularly JAK3, are therapeutically useful. These conditions include,but are not limited to, leukemia, lymphoma, transplant rejection (e.g.,pancreas islet transplant rejection, heart transplant rejection, kidneytransplant rejection, liver transplant rejection, lung transplantrejection), bone marrow transplant applications (e.g., graft-versus-hostdisease), autoimmune diseases (e.g., diabetes), and inflammation (e.g.,asthma, allergic reactions, ocular disorders). Given the severity andprevalence of these diseases and conditions, new therapies are needed.

Compounds

The compounds, and salts thereof, described herein are generallypyrimidine 2,4-diamines, substituted at the 5-position with variousgroups; substituted at the 2-amine with various optionally substitutedaromatic groups; and substituted at the 4-amine with one of a benzooxazol-2(3H)-one, a 1H-benzo[d]imidazol-2(3H)-one, abenzo[d]thiazol-2(3H)-one, a benzo[d][1,3]dithiol-2-one, abenzo[d][1,3]oxathiol-2-one, a benzo[d][1,3]dioxol-2-one, a[1,3]oxathiolo[4,5-b]pyridin-2-one, a thiazolo[5,4-b]pyridin-2(1H)-one,a oxazolo[5,4-b]pyridin-2(1H)-one, a [1,3]oxathiolo[5,4-b]pyridin-2-one,a thiazolo[4,5-b]pyridin-2(3H)-one, a oxazolo[4,5-b]pyridin-2(3H)-one, a[1,3]dioxolo[4,5-b]pyridin-2-one, a [1,3]dithiolo[4,5-b]pyridin-2-one, a1H-imidazo[4,5-b]pyridin-2(3H)-one, a[1,3]oxathiolo[4,5-b]pyrazin-2-one, a thiazolo[5,4-b]pyrazin-2(3H)-one,a oxazolo[5,4-b]pyrazin-2(3H)-one, a [1,3]dioxolo[4,5-b]pyrazin-2-one, a[1,3]dithiolo[4,5-b]pyrazin-2-one and a1H-imidazo[4,5-b]pyrazin-2(3H)-one; each optionally substituted with oneor more groups including prodrug moieties as described herein. Besidesthe groups described above, the N2- and N4-amines of thepyrimidinediamine system may also have optionally substituted alkylgroups and/or prodrug groups.

More specifically, exemplary disclosed compounds are described in termsof formula I:

where:

-   -   X and Y are each independently O, S, S(O), SO₂ or NR¹;    -   each R¹ is independently for each occurrence H, optionally        substituted C₁₋₆alkyl, C(O)—C₁₋₆alkyl, CO₂—C₁₋₆alkyl or R⁵⁰;    -   each R⁵⁰ is —C(R⁹)₂-A-R¹⁰, where A is O or S; each R⁹ is        independently for each occurrence H, optionally substituted        C₁₋₆alkyl, optionally substituted C₆₋₁₀aryl or optionally        substituted C₇₋₁₆arylalkyl; or alternatively, two R⁹, together        with the carbon to which they are attached, form an optionally        substituted C₃₋₈cycloalkyl group or an optionally substituted        3-8 membered heteroalicyclyl; R¹⁰ is R^(a) or —P(O)(OR¹¹)₂; each        R¹¹ is independently for each occurrence R^(a) or a monovalent        cationic group; or two R¹¹, together with the atoms to which        they are attached, form a 4-8 membered cyclic phosphate group,        or two R¹¹ together represent a divalent cationic group;    -   ring A is a C₆₋₁₀aryl or a 5-10 membered heteroaryl;    -   each R² is independently for each occurrence H, R^(e), R^(b),        R^(e) substituted with one or more of the same or different        R^(a) and/or R^(b), —OR^(e) substituted with one or more of the        same or different R^(a) and/or R^(b), —SR^(e) substituted with        one or more of the same or different R^(a) and/or R^(b),        —C(O)R^(e) substituted with one or more of the same or different        R^(a) and/or R^(b), —N(R^(a))R^(e) where R^(e) is substituted        with one or more of the same or different R^(a) and/or R^(b),        —S(O)₂R^(e) substituted with one or more of the same or        different R^(a) and/or R^(b), —N(R^(a))—S(O)₂R^(e) where R^(e)        is substituted with one or more of the same or different R^(a)        and/or R^(b), —B(OR^(a))₂, —B(N(R^(c))₂)₂,        —(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(a))₂)_(m)—R^(b),        —S—(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(b))₂)_(m)—R^(a),        —N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),        —C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —O—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N((C(R^(a))₂)_(m)R^(b))₂,        —S—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N(R^(a))—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N(R^(a))—C(O)—C(R^(a))₂)_(m)—C(R^(a))(R^(b))₂ or        —N(R^(a))—(C(R^(a))₂)_(m)—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b);    -   each R^(a) is independently for each occurrence H, deuterium,        C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,        C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-10 membered        heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15        membered heteroaryl or 6-16 membered heteroarylalkyl;    -   each R^(b) is independently for each occurrence ═O, —OR^(a),        —O—(C(R^(a))₂)_(m)—OR^(a), haloC₁₋₃alkyloxy, ═S, —SR^(a),        ═NR^(a), ═NOR^(a), —N(R^(c))₂, halo, —CF₃, —CN, —NC, —OCN, —SCN,        —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O)₂R^(a), —SO₃R^(a),        —S(O)N(R^(c))₂, —S(O)₂N(R^(c))₂, —OS(O)R^(a), —OS(O)₂R^(a),        —OSO₃R^(a), —OS(O)₂N(R^(c))₂, —C(O)R^(a), —CO₂R^(a),        —C(O)N(R^(c))₂, —C(NR^(a))—N(R^(c))₂, —C(NOH)—R^(a),        —C(NOH)—N(R^(c))₂, —OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(c))₂,        —OC(NH)—N(R^(c))₂, —OC(NR^(a))—N(R^(c))₂, —N(R^(a))—S(O)₂H,        —[N(R^(a))C(O)]_(n)R^(a), —[N(R^(a))C(O)]_(n)OR^(a),        —[N(R^(a))C(O)]_(n)N(R^(c))₂ or        —[N(R^(a))C(NR^(a))]_(n)—N(R^(c))₂;    -   each R^(c) is independently for each occurrence R^(a), or,        alternatively, two R^(c) are taken together with the nitrogen        atom to which they are bonded to form a 3 to 10-membered        heteroalicyclyl or a 5-10 membered heteroaryl which may        optionally include one or more of the same or different        additional heteroatoms and which is optionally substituted with        one or more of the same or different R^(a) and/or R^(d) groups;    -   each R^(d) is ═O, —OR^(a), haloC₁₋₃alkyloxy, C₁₋₆alkyl, ═S,        —SR^(a), ═NR^(a), ═NOR^(a), —N(R^(a))₂, halo, —CF₃, —CN, —NC,        —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O₂)R^(a),        —SO₃R^(a), —S(O)N(R^(a))₂, —S(O)₂N(R^(a))₂, —OS(O)R^(a),        —OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(a))₂, —C(O)R^(a),        —CO₂R^(a), —C(O)N(R^(a))₂, —C(NR^(a))N(R^(a))₂, —C(NOH)R^(a),        —C(NOH)N(R^(a))₂, —OCO₂R^(a), —OC(O)N(R^(a))₂,        —OC(NR^(a))N(R^(a))₂, —[N(R^(a))C(O)]_(n)R^(a),        —(C(R^(a))₂)_(n)—OR^(a), —N(R^(a))—S(O)₂R^(a),        —C(O)—C₁₋₆haloalkyl, —S(O)₂C₁₋₆haloalkyl, —OC(O)R^(a),        —O(C(R^(a))₂)_(m)—OR^(a), —S(C(R^(a))₂)_(m)—OR^(a),        —N(R^(a))C₁₋₆haloalkyl, —P(O)(OR^(a))₂,        —N(R^(a))—(C(R^(a))₂)_(m)—OR^(a), —[N(R^(a))C(O)]_(n)OR^(a),        —[N(R^(a))C(O)]_(n)N(R^(a))₂, —[N(R^(a))C(NR^(a))]N(R^(a))₂ or        —N(R^(a))C(O)C₁₋₆haloalkyl; two R^(d), taken together with the        atom or atoms to which they are attached, combine to form a 3-10        membered partially or fully saturated mono or bicyclic ring,        optionally containing one or more heteroatoms and optionally        substituted with one or more R^(a);    -   each R^(e) is independently for each occurrence C₁₋₆alkyl,        C₃₋₈cycloalkyl, C₄₋₁₁ cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆        arylalkyl, 2-6 membered heteroalkyl, 3-10 membered        heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15        membered heteroaryl or 6-16 membered heteroarylalkyl;    -   p is 0, 1, 2, 3 or 4;    -   each m is 1, 2 or 3;    -   each n is 0, 1, 2 or 3;    -   two R² groups, taken together with the atom or atoms to which        they are attached, combine to form a 4-10 membered partially or        fully saturated mono or bicyclic ring, optionally containing one        or more heteroatoms and optionally substituted with one or more        R^(a) and/or R^(b);    -   Z¹ and Z² are each independently CH, CR² or N;    -   R³ is H, optionally substituted C₁₋₆alkyl or R⁵⁰;    -   R⁴ is H, optionally substituted C₁₋₆alkyl or R⁵⁰; and    -   R⁵ is halo, —CN, optionally substituted C₁₋₆alkyl, alkynyl,        hydroxy, optionally substituted C₁₋₆alkoxy, nitro, —N(R^(a))₂,        —C(O)N(R^(a))₂, —CO₂R^(a) or —C(O)R^(a).

In one embodiment, the compounds of structural formula I are compoundswhere ring A is a phenyl or a pyridyl substituted with one or moregroups. In one embodiment, ring A is a phenyl with at least one grouppara to N4 of the pyrimidinediamine. In another embodiment, ring A is apyridyl with at least one group para to N4 of the pyrimidinediamine. Ina more specific embodiment, ring A is a pyridin-3-yl (where N4 of thepyrimidinediamine is at the 3-yl position) with at least one group parato N4 of the pyrimidinediamine. In another more specific embodiment,ring A is a pyridin-2-yl (where N4 of the pyrimidinediamine is at the2-yl position) with at least one group para to N4 of thepyrimidinediamine. In other embodiments, meta groups can replace oraugment the para groups of the above described embodiments. In all ofthe above embodiments, the groups at the para and/or meta positions caninclude nitrogen, for example an optionally substituted amine, eitherdirectly attached to ring A or in some embodiments tethered to ring Avia an alkylene. Such optionally substituted amines include thosedefined by —N(R^(c))₂ as in relation to formula I. In a specificembodiment, an optionally substituted amine is tethered to ring A via aC₁₋₆alkylene. In an even more specific embodiment, the optionallysubstituted amine is tethered to ring A via a C₁₋₃alkylene and theamine, —N(R^(c))₂ as in relation to formula I, is itself substitutedwith a —N(R^(c))₂ group.

As mentioned, certain presently disclosed compounds have structuralformula I where ring A is a phenyl substituted with one or more R²groups. Thus, in one embodiment, disclosed compounds have formula IA:

where the variables are as described with respect to formula I, andfurther: X and Y are each independently O or NR¹; each R¹ is H,optionally substituted C₁₋₆alkyl or R⁵⁰; each of R^(2a), R^(2b), R^(2c)and R^(2d) is independently for each occurrence as defined for R²; andR⁵ is halo, —CN, optionally substituted C₁₋₆alkyl, nitro, —N(R^(a))₂,—C(O)N(R^(a))₂, —CO₂R^(a) or —C(O)R^(a).

One embodiment is a compound of structural formula IA, where X and Y areeach independently NR¹. In more specific embodiment, X and Y are eachindependently NH or NC₁₋₆alkyl. In an even more specific embodiment, Xand Y are each independently NH or NCH₃. In one embodiment, where X andY are defined more specifically as mentioned, R⁵ is halo or C₁₋₆alkyl;Z¹ is C—H, C-halo or C-optionally substituted C₁₋₆alkyl; and Z² is CH.In a more specific embodiment, R^(2c) and R^(2d) are H; and R⁵ is F orCH₃. In an even more specific embodiment, each of R^(2a) and R^(2b) isindependently for each occurrence H, C₁₋₆alkyl, —OR^(a), —OCF₃, —SR^(a),—N(R^(c))₂, halo, —OCF₂H, —OCH₂F, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a)or —[N(R^(a))C(O)]_(n)R^(a); and one of R^(2a) and R^(2b) is not H. Inanother more specific embodiment, each of R^(2a) and R^(2b) isindependently for each occurrence H, —N(R^(c))₂, halo, —CF₃, —CN,—S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂ or—N(R^(a))—S(O)₂R^(a). In another specific embodiment, R^(2a) is H, haloor cyano; and R^(2b) is halo, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a),—C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂ or —N(R^(a))—S(O)₂R^(a). Inanother specific embodiment, R^(2a) is halo, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂ or—N(R^(a))—S(O)₂R^(a); and R^(2b) is H, halo or cyano.

In another embodiment, disclosed is a compound according to structuralformula IA, where one of X and Y is O and the other is NR¹. In aspecific embodiment, the compound is according to either formula IA1 orIA2:

where R^(2d) is H; R⁵ is halo or C₁₋₆alkyl; Z¹ is CH, C-halo orC-optionally substituted C₁₋₆alkyl; and Z² is CH.

Another embodiment is a compound of structural formulae IA1 or IA2,where R⁵ is F or CH₃. In a more specific embodiment, each of R^(2a),R^(2b) and R^(2c) is independently for each occurrence C₁₋₆alkyl,—OR^(a), —OCF₃, —SR^(a), —N(R^(c))₂, halo, —OCF₂H, —OCH₂F, —CF₃, —CN,—S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂,—(C(R^(a))₂), R^(b), —N(R^(a))—S(O)₂R^(a) or —[N(R^(a))C(O)]_(n)R^(a).In another more specific embodiment, R^(2a), R^(2b) and R^(2c) are eachindependently C₁₋₆alkyl, —OR^(a), —OCF₃, halo, —CF₃ or —CN. In oneembodiment, R^(2a) is CH₃; R^(2b) is halo; and R^(2c) is CH₃. In anotherembodiment, R^(2a) is CH₃; R^(2b) is CH₃; and R^(2c) is halo. In anotherembodiment, R^(2a) is CH₃; R^(2b) is CH₃; and R^(2c) is CH₃. In a morespecific embodiment, R^(2a) is CH₃; R^(2b) is CH₃ and R^(2c) is CH₃, R⁵is CH₃.

Another embodiment is a compound of structural formulae IA1, where R⁵ isCH₃, and each of R^(2a), R^(2b) and R^(2c) is independently for eachoccurrence C₁₋₆alkyl, haloC₁₋₆alkyl, —OR^(a), —OCF₃, —SR^(a),—N(R^(c))₂, halo, —OCF₂H, —OCH₂F, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a),—C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂, —(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—S(O)₂R^(a) or —[N(R^(a))C(O)]_(n)R^(a). In another morespecific embodiment, R^(2a), R^(2b) and R^(2c) are each independentlyC₁₋₆alkyl, —OR^(a), —OCF₃, halo, —CF₃ or —CN. In one embodiment, R^(2a)is CH₃; R^(2b) is halo; and R^(2c) is CH₃. In another embodiment, R^(2a)is CH₃; R^(2b) is CH₃; and R^(2c) is halo. In another embodiment, eachof R^(2a), R^(2b) and R^(2c) is independently for each occurrenceC₁₋₆alkyl or haloC₁₋₆alkyl. In another embodiment, each of R^(2a),R^(2b) and R^(2c) is independently for each occurrence C₁₋₆alkyl. In amore specific embodiment, R^(2a) is CH₃; R^(2b) is CH₃ and R^(2c) isCH₃.

Another embodiment is a compound of structural formulae IA1 or IA2,where R^(2b) is H; R⁵ is F or CH₃. In a more specific embodiment, eachof R^(2a) and R^(2c) is independently for each occurrence H, C₁₋₆alkyl,—OR^(a), —OCF₃, —SR^(a), —N(R^(c))₂, halo, —OCF₂H, —OCH₂F, —CF₃, —CN,—S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂,—N(R^(a))—S(O)₂R^(a), —C(R^(a))₂—N(R^(c))₂ or —[N(R^(a))C(O)]_(n)R^(a);and one of R^(2a) and R^(2c) is not H. In another embodiment, each ofR^(2a) and R^(2c) is independently for each occurrence H, C₁₋₆alkyl,—OR^(a), —OCF₃, halo, —CF₃, —C(R^(a))₂—N(R^(c))₂ or —CN. In anotherembodiment, R^(2a) is —CF₃ or —CH₃; and R^(2c) is halo or —CH₃. Inanother embodiment, R^(2a) is H, —CH₃, —CF₃, —OR^(a) or —OCF₃; andR^(2c) is —C(R^(a))₂—N(R^(c))₂.

Another embodiment is a compound of structural formula IA1 or IA2, whereR^(2c) is H; and R⁵ is F or CH₃. In one specific embodiment each ofR^(2a) and R^(2b) is H, C₁₋₆alkyl, —OR^(a), —OCF₂H, —OCH₂F, —OCF₃,—SR^(a), —N(R^(c))₂, halo, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a),—C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a),—C(R^(a))₂—N(R^(c))₂ or —[N(R^(a))C(O)]R^(a); and one of R^(2a) andR^(2b) is not H. In another embodiment, each of R^(2a) and R^(2b) is H,C₁₋₆alkyl, —OR^(a), —OCF₃, halo, —N(R^(c))₂, —CF₃, —C(R^(a))₂—N(R^(c))₂or —CN. In another embodiment, R^(2b) is —CF₃ or —CH₃; and R^(2a) ishalo or —CH₃. In another embodiment, R^(2a) is H, —CH₃, —CF₃, —OR^(a) or—OCF₃; and R^(2b) is —N(R^(c))₂ or —C(R^(a))₂—N(R^(c))₂. In yet anotherembodiment, R^(2a) is —N(R^(c))₂ or —C(R^(a))₂—N(R^(c))₂; and R^(2b) isH, —CH₃, —CF₃, —OR^(a) or —OCF₃.

Still another embodiment is a compound of structural formulae IA1 orIA2, where R^(2c) and R^(2d) are H, and R⁵ is F or CH₃; R^(2a) andR^(2b) are taken together with the carbons to which they are attached toform a 4-10 membered partially or fully saturated mono or bicyclic ring,optionally containing one or more heteroatoms and optionally substitutedwith one or more R^(a) and/or R^(b). In one embodiment, this is a 5membered ring, and in a more specific embodiment the 5 membered ring iscyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine ortetrahydrofuran; optionally substituted with one or more R^(a) and/orR^(b). In a specific embodiment, the 5 membered ring is pyrrolidine, andin an even more specific embodiment the compounds are according toformula IA3:

where R^(b) is OH, C₁₋₆alkyl, —CO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl or—S(O)₂C₁₋₆alkyl. In another embodiment, R^(2a) and R^(2b) are takentogether with the carbons to which they are attached to form a 6, 7 or 8membered partially or fully saturated monocyclic ring, optionallycontaining one or more heteroatoms and optionally substituted with oneor more R^(a) and/or R^(b). In one embodiment, when the ring is 6membered, the ring is cyclohexane, morpholine, piperidine, dioxane,oxathiazinane or piperazine; optionally substituted with one or moreR^(a) and/or R^(b). In another embodiment, when the ring is 7 membered,the ring is cycloheptane, cycloheptene, azepane, tetrahydroazepine ordiazepane; optionally substituted with one or more R^(a) and/or R^(b).In yet another embodiment, when the ring is 8 membered, the ring iscyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane orhexahydrodiazocine; optionally substituted with one or more R^(a) and/orR^(b). For each of the above embodiments, where R^(2a) and R^(2b) aretaken together with the carbons to which they are attached to form a 5,6, 7 or 8 membered partially or fully saturated monocyclic ring, thereis a more specific embodiment where there are 0, 1, 2 or 3 each of R^(a)and R^(b), and R^(a) is C₁₋₆alkyl; and each R^(b) is independently foreach occurrence ═O, —OR^(a), haloC₁₋₃alkyloxy, —SR^(a), —N(R^(c))₂,halo, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a),—C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a) or —C(R^(a))₂—N(R^(c))₂. Forexample, in one embodiment, there is at least one R^(b) that is ═O; andoptionally an R^(a) that is optionally substituted C₁₋₆alkyl. Particularexamples of compounds according to formula IA3, include, withoutlimitation, compounds such as IV-2, IV-10, IV-14 through IV-16, IV-18through IV-34, and IV-50 are encompassed (see Table IV).

Some embodiments include compounds where ring A is other than phenyl. Ina specific embodiment, ring A is pyridine or pyridazine. As shown informula I, and with respect to this embodiment, the pyridine orpyridazine can have various regiochemical configurations and points ofattachment to the parent molecule. One embodiment of the compounds ofstructural formula I, are compounds according to formula IB:

where the variables are defined in the same way as for the those offormula I, and further: Q¹ and Q² are each independently N or CR²,provided at least one of Q¹ and Q² is N; X and Y are each independentlyO or NR¹; each R¹ is independently for each occurrence H, optionallysubstituted C₁₋₆alkyl or R⁵⁰; p is 0, 1, 2 or 3; and R⁵ is halo, —CN,optionally substituted C₁₋₆alkyl, nitro, —N(R^(a))₂, —C(O)N(R^(a))₂,—CO₂R^(a) or —C(O)R^(a).

One embodiment of the compounds of structural formula IB, is a compoundaccording to formula IB1 or IB2:

where each of R^(2a), R^(2b), R^(2c) and R^(2d) (when present) isindependently for each occurrence as defined for R².

One embodiment is a compound of structural formula IB1 or IB2, where Xand Y are each independently NR¹. In a more specific embodiment, X and Yare each independently NH or NC₁₋₆alkyl. In an even more specificembodiment, X and Y are each independently NH or NCH₃. In oneembodiment, where X and Y are defined more specifically as mentioned, R⁵is halo or C₁₋₆alkyl; Z¹ is CH, C-Halo or C-optionally substitutedC₁₋₆alkyl; and Z² is CH. In another embodiment, R^(2a) and R^(2d) are H;and R⁵ is F or CH₃. In another embodiment, each of R^(2b) and R^(2c) isindependently for each occurrence H, C₁₋₆alkyl, —OR^(a), —OCH₂F, —OCF₃,—SR^(a), —N(R^(c))₂, halo, —OCF₂H, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂,—N(R^(a))—S(O)₂R^(a), —C(R^(a))₂—N(R^(c))₂ or —[N(R^(a))C(O)]_(n)R^(a);and one of R^(2b) and R^(2c) is not H. In another such embodiment, eachof R^(2b) and R^(2c) is independently for each occurrence H, C₁₋₆alkyl,—N(R^(c))₂, halo, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a),—CO₂R^(a), —C(O)N(R^(c))₂, —C(R^(a))₂—N(R^(c))₂ or —N(R^(a))—S(O)₂R^(a).In another embodiment, R^(2b) is H, halo, —CF₃, —CN or —CH₃; and R^(2c)is —N(R^(c))₂, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)N(R^(c))₂ or—C(R^(a))₂—N(R^(c))₂.

Another embodiment is a compound of structural formula IB1 or IB2, whereX is O and Y is NR¹. In one embodiment, R⁵ is halo or C₁₋₆alkyl; Z¹ isCH, C-Halo or C-optionally substituted C₁₋₆alkyl; and Z² is CH. Inanother embodiment, R^(2a) and R^(2d) are H; and R⁵ is F or CH₃. In amore specific embodiment, each of R^(2b) and R^(2c) is independently foreach occurrence H, C₁₋₆alkyl, —OR^(a), —OCF₃, —SR^(a), —N(R^(c))₂, halo,—OCF₂H, —OCH₂F, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a),—CO₂R^(a), —C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a), —C(R^(a))₂—N(R^(c))₂ or—[N(R^(a))C(O)]_(n)R^(a); and one of R^(2b) and R^(2c) is not H. Inanother embodiment, each of R^(2b) and R^(2c) is independently for eachoccurrence H, C₁₋₆alkyl, —N(R^(c))₂, halo, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂, —C(R^(a))₂—N(R^(c))₂or —N(R^(a))—S(O)₂R^(a). In a more specific embodiment R^(2b) is H,halo, —CF₃, —CN or —CH₃; and R^(2c) is —N(R^(c))₂, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)N(R^(c))₂ or —C(R^(a))₂—N(R^(c))₂. In anotherembodiment, R^(2b) is H, halo, —CF₃, —CN or —CH₃; and R^(2c) is—N(R^(c))₂ or —C(R^(a))₂—N(R^(c))₂.

Another embodiment is a compound of structural formula IB1 or IB2, whereX is O; Y is NR¹; Z¹ is CH, C-Halo or C-optionally substitutedC₁₋₆alkyl; Z² is CH; R^(2a) and R^(2d) are H; and R⁵ is F or CH₃, R^(2b)and R^(2c) are taken together with the carbons to which they areattached to form a 4-10 membered partially or fully saturated mono orbicyclic ring, optionally containing one or more heteroatoms andoptionally substituted with one or more R^(a) and/or R^(b). In oneembodiment, the ring is a 5, 6, 7 or 8 membered partially or fullysaturated monocyclic ring optionally substituted with one or more R^(a)and/or R^(b). In one embodiment, the 5, 6, 7 or 8 membered partially orfully saturated monocyclic ring is cyclopentane, pyrrolidine,imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane,morpholine, piperidine, dioxane, oxathiazinane, piperazine,cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane,cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane orhexahydrodiazocine; optionally substituted with one or more R^(a) and/orR^(b). For each of the above embodiments, where R^(2b) and R^(2c) aretaken together with the carbons to which they are attached to form a 5,6, 7 or 8 membered partially or fully saturated monocyclic ring, thereis a more specific embodiment where there are 0, 1, 2 or 3 each of R^(a)and R^(b), and R^(a) is C₁₋₆alkyl; and each R^(b) is independently foreach occurrence ═O, —OR^(a), haloC₁₋₃alkyloxy, —SR^(a), —N(R^(c))₂,halo, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a),—C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a) or —C(R^(a))₂—N(R^(c))₂. Forexample, in one embodiment, there is at least one R^(b) that is ═O; andoptionally an R^(a) that is optionally substituted C₁₋₆alkyl. In thisembodiment compounds such as IV-45, IV-46 and IV-47 are encompassed (seeTable IV).

Another embodiment of the compounds of structural formula IB, is acompound according to formula IB3:

wherein each of R^(2a), R^(2b) and R^(2c) is independently for eachoccurrence as defined for R².

One embodiment is a compound of structural formula IB3, where X is O andY is NR¹. In one embodiment, R⁵ is halo or C₁₋₆alkyl; Z¹ is CH, C-Haloor C-optionally substituted C₁₋₆alkyl; and Z² is CH. In anotherembodiment, R^(2a) is H; and R⁵ is F or CH₃. In a more specificembodiment, each of R^(2b) and R^(2c) is independently for eachoccurrence H, C₁₋₆alkyl, —OR^(a), —OCF₃, —SR^(a), —N(R^(c))₂, halo,—OCF₂H, —OCH₂F, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a),—CO₂R^(a), —C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a), —C(R^(a))₂—N(R^(c))₂ or—[N(R^(a))C(O)]_(n)R^(a); and one of R^(2b) and R^(2c) is not H. Inanother embodiment, each of R^(2b) and R^(2c) is independently for eachoccurrence H, C₁₋₆alkyl, —N(R^(c))₂, halo, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂, —C(R^(a))₂—N(R^(c))₂or —N(R^(a))—S(O)₂R^(a). In a more specific embodiment R^(2b) is H,halo, —CF₃, —CN or —CH₃; and R^(2c) is —N(R^(c))₂, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)N(R^(c))₂ or —C(R^(a))₂—N(R^(c))₂. In anotherembodiment, R^(2b) is H, halo, —CF₃, —CN or —CH₃; and R^(2c) is—N(R^(c))₂ or —C(R^(a))₂—N(R^(c))₂.

Another embodiment is a compound of structural formula IB3, where X isO; Y is NR¹; Z¹ is CH, C-Halo or C-optionally substituted C₁₋₆alkyl; Z²is CH; R^(2c) and R^(2d) are H; and R⁵ is F or CH₃, R^(2b) and R^(2c)are taken together with the carbons to which they are attached to form a4-10 membered partially or fully saturated mono or bicyclic ring,optionally containing one or more heteroatoms and optionally substitutedwith one or more R^(a) and/or R^(b). In one embodiment, the ring is a 5,6, 7 or 8 membered partially or fully saturated monocyclic ringoptionally substituted with one or more R^(a) and/or R^(b). In oneembodiment, the 5, 6, 7 or 8 membered partially or fully saturatedmonocyclic ring is cyclopentane, pyrrolidine, imidazolidine,1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine,piperidine, dioxane, oxathiazinane, piperazine, cycloheptane,cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane,cyclooctene, azocane, hexahydroazocine, diazocane or hexahydrodiazocine;optionally substituted with one or more R^(a) and/or R^(b). For each ofthe above embodiments, where R^(2b) and R^(2c) are taken together withthe carbons to which they are attached to form a 5, 6, 7 or 8 memberedpartially or fully saturated monocyclic ring, there is a more specificembodiment where there are 0, 1, 2 or 3 each of R^(a) and R^(b), andR^(a) is C₁₋₆alkyl; and each R^(b) is independently for each occurrence═O, —OR^(a), haloC₁₋₃alkyloxy, —SR^(a), —N(R^(c))₂, halo, —CF₃, —CN,—S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂,—N(R^(a))—S(O)₂R^(a) or —C(R^(a))₂—N(R^(c))₂.

Another embodiment is a compound of structural formula I, where ring Ais indazole, benzoxazole, pyrazolopyridine or isoxozolopyridine; X is O;Y is NR¹; R⁵ is halo or C₁₋₆alkyl; Z¹ is CH, C-Halo or C-optionallysubstituted C₁₋₆alkyl; Z² is CH; and each R² is independently for eachoccurrence H, C₁₋₆alkyl, —OR^(a), —OCF₃, —SR^(a), —N(R^(c))₂, halo,—OCF₂H, —OCH₂F, —CF₃, —CN, —S(O)₂N(R^(c))₂, —S(O)₂R^(a), —C(O)R^(a),—CO₂R^(a), —C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a) or—[N(R^(a))C(O)]_(n)R^(a).

Another embodiment of the compounds of structural formula I, is acompound according to formula II:

where the variables are defined in the same way as for the those offormula I, and further: two of R² combine to form ring B; ring B,together with the two phenyl ring atoms to which it is attached, forms a5, 6 or 7-membered ring, optionally containing 1, 2 or 3 heteroatomsindependently selected from N(R^(c)), O and S; R^(a) is C₁₋₆alkyl; andeach R^(b) is independently for each occurrence ═O, —OR^(a),haloC₁₋₃alkyloxy, —SR^(a), —N(R^(c))₂, halo, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂, —N(R^(a))—S(O)₂R^(a)or —C(R^(a))₂—N(R^(c))₂. In one more specific embodiment, Z¹ is CH,C-halo or C-optionally substituted C₁₋₆alkyl. To further aide indescribing ring B, examples of B rings are, disregarding the unit ofunsaturation between the two phenyl ring atoms for simplicity innomenclature only, cyclopentane, pyrrolidine, imidazolidine,1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine,piperidine, dioxane, oxathiazinane, piperazine, cycloheptane,cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane,cyclooctene, azocane, hexahydroazocine, diazocane or hexahydrodiazocine.That is, for example, if ring B is described as “cyclohexane,” then thecompound would be according to formula IIa:

In another example, if ring B is described as “cycloheptene,” then thecompound is according to formulae IIb, IIc, IId or IIe:

Another embodiment is a compound according to formula IA1, where R^(2d)is H; R⁵ is halo or C₁₋₆alkyl; Z¹ is CH, C-halo or C-optionallysubstituted C₁₋₆alkyl; Z² is CH; and each of R^(2a), R^(2b) and R^(2c)is independently for each occurrence C₁₋₆alkyl, —OR^(a), —OCF₃, —SR^(a),—N(R^(c))₂, halo, —OCF₂H, —OCH₂F, —CF₃, —CN, —S(O)₂N(R^(c))₂,—S(O)₂R^(a), —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂,—(C(R^(a))₂)_(m)—R^(b), —N(R^(a))—S(O)₂R^(a) or—[N(R^(a))C(O)]_(n)R^(a), provided one of R^(2a), R^(2b) and R^(2c) is—N(R^(c))₂, —C(O)N(R^(c))₂ or —(C(R^(a))₂)_(m)—R^(b). In a more specificembodiment, R⁵ is F or CH₃. In another embodiment, one of R^(2a), R^(2b)and R^(2c) is —N(R^(c))₂. In another embodiment, one of R^(2a), R^(2b)and R^(2c) is —(C(R^(a))₂)_(m)—R^(b). In a more specific embodiment, R⁵is F or CH₃. In a more specific embodiment, the one of R^(2a), R^(2b)and R^(2c) that is —N(R^(c))₂, is:

optionally substituted with one or more of the same or different R^(a)and/or R^(b) groups. In a more specific embodiment, the one of R^(2a),R^(2b) and R^(2c) that is —(C(R^(a))₂)_(m)—R^(b), is even morespecifically —C(R^(a))₂—N(R^(c))₂. In an even more specific embodiment,the one of R^(2a), R^(2b) and R^(2c) that is —C(R^(a))₂—N(R^(c))₂ is:

optionally substituted with one or more of the same or different R^(a)and/or R^(b) groups.

In one embodiment, at least one R² group is a water-solubilizing group,that is, a group that has hydrophilic character sufficient to improve orincrease the water-solubility of the compound in which it is included,as compared to an analog compound that does not include the group. Thehydrophilic character can be achieved by, for example, the inclusion offunctional groups that ionize under the conditions of use to formcharged moieties (e.g., carboxylic acids, sulfonic acids and salts,phosphoric acids and salts, amines, etc.); groups that include permanentcharges (e.g., quaternary ammonium groups); and/or heteroatoms orheteroatomic groups. For example, —O—(C(R^(a))₂)_(m)—R^(b),—S—(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(b))₂)_(m)—R^(a),—N(R^(a))—(C(R^(a))₂)_(m)—R^(b), —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b) and —N((C(R^(a))₂)_(m)R^(b))₂. Morespecific examples include —O—C₁₋₆alkylene-R^(b), —S—C₁₋₆alkylene-R^(b),—O—C₁₋₆alkylene-R^(a) where R^(a) is heterocyclyl,—N(R^(a))—C₁₋₆alkylene-R^(b), —O—C₁₋₆alkylene-CH((CH₂)₁₋₂R^(b))R^(b),—C(O)N(R^(a))—C₁₋₆alkylene-R^(b) and —N((C(R^(a))₂)₁₋₃R^(b))₂. Even morespecific examples include —O—C₁₋₄alkylene-R^(b), —S—C₁₋₄alkylene-R^(b),—O—C₁₋₄alkylene-R^(a) where R^(a) is heterocyclyl,—N(H)—C₁₋₄alkylene-R^(b), —O—C₁₋₄alkylene-CH((CH₂)₁₋₂R^(b))R^(b),—C(O)N(H)—C₁₋₄alkylene-R^(b) and —N((CH₂)₁₋₃R^(b))₂. In another specificexample, in accord with the formula given above for water solubilizinggroups, the water solubilizing group is an amino acid tethered from themolecule via a bond to the nitrogen of the amino acid. In a morespecific example, a water solubilizing group is an α-amino acid orderivative thereof attached to the parent ring, e.g. ring A and/or at Z¹or Z², via the nitrogen of the α-amino acid, for example—N(H)C(R^(a))₂—R^(b), where R^(b) is —CO₂R^(a) or —C(O)N(R^(c))₂. Inanother specific embodiment, the water-solubilizing group is morpholino,piperidinyl, N—C₁₋₆alkyl piperidinyl, piperazinyl, N—C₁₋₆alkylpiperazinyl, pyrrolidinyl, N—C₁₋₆alkyl pyrrolidinyl, diazepinyl,N—C₁₋₆alkyl azepinyl, homopiperazinyl, N—C₁₋₆alkyl homopiperazinyl,imidazoyl, and the like. In another example the water-solubilizing groupis one of the aforementioned rings tethered to the parent molecule viaan alkylene, alkylidene, alkylidyne linker. In a more specificembodiment, the water-solubilizing group is one of the aforementionedrings tethered to the parent molecule via a C₁₋₆alkylene, where one ortwo of the alkylene carbons is, independently, replaced with one of O, Sor NH, but not where any two of the aforementioned heteroatoms arecontiguous in the linker. Other water solubilizing groups are well-knownand include, by way of example, hydrophilic groups such as alkyl orheteroalicyclyl groups substituted with one or more of an amine,alcohol, a carboxylic acid, a phosphorous acid, a sulfoxide, acarbohydrate, a sugar alcohol, an amino acid, a thiol, a polyol, anether, a thioether, and a quaternary amine salt.

For each of the above embodiments of the compounds of structuralformulae I, IA, IA1, IA2, IA3, IB, IB1, IB2, IB3 and II, there isanother embodiment where R¹ is H or R⁵⁰; R⁵⁰ is —CH₂OP(O)(OR¹¹)₂; andeach R¹¹ is independently for each occurrence R^(a) or a monovalentcationic group; or two R¹¹, together with the atoms to which they areattached, form a 4-8 membered cyclic phosphate group, or two R¹¹together represent a divalent cationic group. Also, for each of theseembodiments, there is a more specific embodiment where each R¹¹ isindependently for each occurrence H, t-butyl, or a pharmaceuticallyacceptable cation, such as HOCH₂CH₂N(CH₃)₃ ⁺, Na⁺, Li⁺ or K⁺.

As mentioned, the 2,4-pyrimidinediamine compounds and prodrugs, as wellas the salts thereof, can also be in the form of hydrates, solvates, andN-oxides, as is well-known in the art. One embodiment is apharmaceutically acceptable salt form of a compound of formula I. Thepharmaceutically acceptable salts of the present invention can be formedby conventional means, such as by reacting the free base form of theproduct with one or more equivalents of the appropriate acid in asolvent or medium in which the salt is insoluble or in a solvent such aswater which is removed in vacuo, by freeze drying, or by exchanging theanions of an existing salt for another anion on a suitable ion exchangeresin. The present invention includes within its scope solvates of the2,4-pyrimidinediamine compounds and salts and hydrates thereof, forexample, a hydrated formate salt.

In another embodiment, disclosed herein are compounds selected fromTables I-IV, or a stereoisomer, tautomer, prodrug, solvate, orpharmaceutically acceptable salt thereof. Many compounds describedherein were made both as the parent and at least one salt form. Somespecific salts made, referred to by their designation from Tables I-IV,include the calcium salt: compound I-517; the mono-choline salt:compound I-414; the bis-choline salt: compound I-531; the formate salt:compounds I-7 through I-10, I-43, I-46, I-47, I-49, I-50, I-51, I-53,I-54, I-56, I-127, I-128, I-132, I-134, I-137, I-138, I-140, I-153through I-158, I-165 through I-169, I-172 through I-190, I-201 throughI-239, I-241, I-271, I-272, I-423, I-433, I-438 through I-442, I-445,I-446, I-455 through I-457, I-460, I-463 through I-468, I-470, I-473,I-486, I-487, I-494, I-498, I-499 through I-504, I-513 through I-515,I-518, I-519, I-527, I-530, II-4, II-5, II-6, II-8, II-9, II-11, II-12,II-42, II-43, II-48, II-49, II-53, II-55 through II-70, II-78, II-79,II-151, III-12, III-14, IV-3, IV-10, IV-11, IV-14, IV-17, IV-18, IV-19,IV-21, IV-31, IV-32 and IV-60 through I-62; the diformate salt,compounds II-3, II-46, II-47, II-51, II-52 and II-54; themonotrifluoroacetate salt, compounds I-11 through I-16, I-27, I-28, I-30through I-32, I-34 through I-38, I-52, I-55, I-57 through I-95, I-104through I-109, I-115, I-129, I-130, I-131, I-135, I-136, I-141, I-142,I-145, I-149, I-159, I-160 through I-164, I-171, I-191, I-192, I-193,I-195 through I-200, I-242 through I-254, I-256 through I-262, I-264through I-269, I-273, I-274, I-403, I-404, I-419 through I-422, I-427through I-432, I-447 through I-449, I-452 through I-454, I-458, I-469,I-474 through I-477, I-488 through I-492, I-507, I-508, I-520, I-521,I-529, I-535, II-7, IV-12, IV-13, IV-15, IV-16, IV-22 through IV-30,IV-33, IV-34, IV-51, IV-52, IV-53, IV-54, IV-59 and IV-64; theditrifluoroacetate salt, compounds I-120 through I-123, I-255, I-263,I-270, I-426, I-459, II-17, II-19, II-38, II-45, II-71, II-74, II-76,II-77, II-87, II-93, II-100, II-101, II-102, II-150 and IV-20; thebenzene sulfonic acid salt, compound I-393; the p-toluene sulfonic acidsalt: compound I-409; the sulfuric acid salt: compound I-411; thehydrochloride salt, compounds I-133 and I-412; the dihydrochloride salt,compound II-44; the disodium salt, compounds I-33, I-358, I-407, I-451,I-528, I-536 and 1-538; the magnesium salt: compound I-526; the mesylatesalt: compound I-410; and the monosodium salt: compounds I-413, I-436and I-437.

As is recognized by one of ordinary skill in the art, the presentformulae include other salt forms in addition to those specificallydescribed herein. Similarly, one of ordinary skill in the art wouldunderstand the presently disclosed formulae to encompass solvates, suchas hydrates.

TABLE I

Cpd X Y Z¹ R⁵ R^(2a) R^(2b) R^(2c) R^(2d) I-1  O NH CH CH₃ C(O)H H H HI-2  O NH CH CH₃ C(O)NH₂ H H H I-3  O NH CH CH₃ H C(O)NH₂ H H I-4  O NHCH CH₃ H C(O)H H H I-5  O NH CH CH₃ CH₃

H H I-6  O NH CH CH₃ F

H H I-7  O N-(n-propyl) CH CH₃ S(O)₂CH₃ H H H I-8  O N-(n-propyl) CH CH₃N(H)S(O)₂CH₃ H H H I-9  O N-(isopropyl) CH CH₃ S(O)₂CH₃ H H H I-10  ON-(isopropyl) CH CH₃ N(H)S(O)₂CH₃ H H H I-11  NH NH CH CH₃ S(O)₂NH₂ H HH I-12  NH NH CH CH₃ H S(O)₂NH₂ H H I-13  NH NH CH F H S(O)₂NH₂ H HI-14  O NH CH CH₃ S(O)₂NH₂ H H H I-15  O NH CH CH₃ H S(O)₂NH₂ H H I-16 O NH CH CH₃ S(O)₂CH₃ H H H I-17  O NH CH CH₃ H S(O)₂CH₃ H H I-18  O NHCH F S(O)₂NH₂ H H H I-19  O NH CH F H S(O)₂NH₂ H H I-20  O NH CH FS(O)₂CH₃ H H H I-21  O NH CH F H S(O)₂CH₃ H H I-22  NH NH CH CH₃S(O)₂CH₃ H H H I-23  NH NH CH F H S(O)₂CH₃ H H I-24  O NH CH CH₃S(O)₂NH₂ CH₃ H H I-25  O NH CH CH₃ S(O)₂N(H)-t-Bu H H H I-26  O NH CHCH₃ CN H H H I-27  O NH CH CH₃ H CN H H I-28  NH NH CH CH₃ CN H H HI-29  NH NH CH CH₃ H CN H H I-30  O NH CH CH₃

H H H I-31  O NH CH F

H H H I-32  NH NH CH F

H H H I-33  O NCH₂OP(O)(OH)₂ CH CH₃ S(O)₂CH₃ H H H I-34  NCH₃ NCH₃ CHCH₃ S(O)₂NH₂ H H H I-35  NCH₃ NCH₃ CH CH₃ H S(O)₂NH₂ H H I-36  NCH₃ NCH₃CH CH₃ S(O)₂CH₃ H H H I-37  NCH₃ NCH₃ CH CH₃ N(H)S(O)₂CH₃ H H H I-38 NCH₃ NCH₃ CH CH₃ H N(H)S(O)₂CH₃ H H I-39  NCH₃ NCH₃ CH F S(O)₂NH₂ H H HI-40  NCH₃ NCH₃ CH F H S(O)₂NH₂ H H I-41  NCH₃ NCH₃ CH F S(O)₂Me H H HI-42  NCH₃ NCH₃ CH F N(H)S(O)₂CH₃ H H H I-43  NCH₃ NCH₃ CH F HN(H)S(O)₂CH₃ H H I-44  O NH CH F CN H H H I-45  O NH CH F H CN H H I-46 O NH CH CH₃ morpholin-4-yl H H H I-47  O NH CH F morpholin-4-yl H H HI-48  NH O CH CH₃ morpholin-4-yl H H H I-49  NCH₃ O CH CH₃morpholin-4-yl H H H I-50  NH NH CH CH₃ H N(H)S(O)₂CH₃ H H I-51  NH NHCH F H N(H)S(O)₂CH₃ H H I-52  O NH CH CH₃ H N(H)S(O)₂CH₃ H H I-53  O NHCH F H N(H)S(O)₂CH₃ H H I-54  NH NH CH CH₃ N(H)S(O)₂CH₃ H H H I-55  O NHCH CH₃ N(H)S(O)₂CH₃ H H H I-56  O NH CH F N(H)S(O)₂CH₃ H H H I-57  NCH₃O CH F S(O)₂NH₂ H H H I-58  NCH₃ O CH F H S(O)₂NH₂ H H I-59  NCH₃ O CH FS(O)₂CH₃ H H H I-60  NCH₃ O CH F H S(O)₂CH₃ H H I-61  NCH₃ O CH FN(H)S(O)₂CH₃ H H H I-62  NCH₃ O CH F H N(H)S(O)₂CH₃ H H I-63  NCH₃ O CHCH₃ S(O)₂NH₂ H H H I-64  NCH₃ O CH CH₃ H S(O)₂NH₂ H H I-65  NCH₃ O CHCH₃ S(O)₂CH₃ H H H I-66  NCH₃ O CH CH₃ H S(O)₂CH₃ H H I-67  O NCH₃ CHCH₃ H S(O)₂NH₂ H H I-68  O NCH₃ CH CH₃ H S(O)₂NH₂ H H I-69  O NCH₃ CHCH₃ S(O)₂CH₃ H H H I-70  O NCH₃ CH CH₃ H S(O)₂CH₃ H H I-71  O NCH₃ CHCH₃ N(H)S(O)₂CH₃ H H H I-72  O NCH₃ CH CH₃ H N(H)S(O)₂CH₃ H H I-73  NCH₃O CH CH₃ N(H)S(O)₂CH₃ H H H I-74  NCH₃ O CH CH₃ H N(H)S(O)₂CH₃ H H I-75 O NCH₃ CH F S(O)₂NH₂ H H H I-76  O NCH₃ CH F H S(O)₂NH₂ H H I-77  O NCH₃CH F S(O)₂CH₃ H H H I-78  O NCH₃ CH F H S(O)₂CH₃ H H I-79  O NCH₃ CH FN(H)S(O)₂CH₃ H H H I-80  O NCH₃ CH F H N(H)S(O)₂CH₃ H H I-81  O NH CHCH₃ N(H)S(O)₂CH₃ CH₃ H H I-82  O NCH₃ CH CH₃ N(H)S(O)₂CH₃ CH₃ H H I-83 NCH₃ O CH CH₃ N(H)S(O)₂CH₃ CH₃ H H I-84  O NH CH F N(H)S(O)₂CH₃ CH₃ H HI-85  O NCH₃ CH F N(H)S(O)₂CH₃ CH₃ H H I-86  NCH₃ O CH F N(H)S(O)₂CH₃CH₃ H H I-87  O NH CH CH₃ N(H)S(O)₂CH₃ F H H I-88  O NCH₃ CH CH₃N(H)S(O)₂CH₃ F H H I-89  NCH₃ O CH CH₃ N(H)S(O)₂CH₃ F H H I-90  O NH CHF N(H)S(O)₂CH₃ F H H I-91  O NCH₃ CH F N(H)S(O)₂CH₃ F H H I-92  NCH₃ OCH F N(H)S(O)₂CH₃ F H H I-93  O NH CH CH₃ H N(CH₃)S(O)₂CH₃ H H I-94  ONCH₃ CH CH₃ H N(CH₃)S(O)₂CH₃ H H I-95  NCH₃ O CH CH₃ H N(CH₃)S(O)₂CH₃ HH I-96  O NH CH F H N(CH₃)S(O)₂CH₃ H H I-97  NCH₃ O CH F HN(CH₃)S(O)₂CH₃ H H I-98  NH O CH CH₃ S(O)₂NH₂ H H H I-99  NH O CH CH₃ HS(O)₂NH₂ H H I-100 NH O CH CH₃ S(O)₂CH₃ H H H I-101 NH O CH CH₃ HS(O)₂CH₃ H H I-102 NH O CH CH₃ N(H)S(O)₂CH₃ H H H I-103 NH O CH CH₃ HN(H)S(O)₂CH₃ H H I-104 NH O CH CH₃ N(H)S(O)₂CH₃ CH₃ H H I-105 NH O CHCH₃ N(H)S(O)₂CH₃ F H H I-106 O NH CH CH₃ OCF₃ H H H I-107 O NH CH F OCF₃H H H I-108 O NH CH CH₃ H OCF₃ H H I-109 O NH CH F H OCF₃ H H I-110 O NHCH CH₃ CF₃

H H I-111 O NH CH CH₃ H

H H I-112 O NH CH CH₃ H S(O)₂N(H)-t-Bu H H I-113 O NH CH CH₃S(O)₂N(H)-t-Bu CH₃ H H I-114 O NH CH CH₃

H H H I-115 O NH CH F OCH₃ OCH₃ OCH₃ H I-116 O NH CH CH₃ OCF₂H OCH₃ H HI-117 O NH CH CH₃ H S(O)₂CF₃ H H I-118 O NH CH CH₃ S(O)₂CF₃ H H H I-119O NH CH CH₃ OCH₃ OCH₃ OCH₃ H I-120 O NH CH CH₃ CH₃

H H I-121 O NH CH CH₃ H

H H I-122 O NH CH CH₃ CH₃

H H I-123 O NH CH CH₃ H

H H I-124 O NH CH CH₃ morpholin-4-yl OCF3 H H I-125 O NH CH CH₃ H CO₂CH₃H H I-126 O NH CH CH₃ H CO₂H H H I-127 O NH CH CH₃ H

H H I-128 O NH CH CH₃ H

H H I-129 O NH CH CH₃ H C(O)CH₃ H H I-130 O NH CH CH₃ C(O)CH₃ H H HI-131 O NH CH CH₃ CN CH₃ H H I-132 O NH CH CH₃ H C(O)N(CH₃)₂ H H I-133 ONH CH CH₃ H C(O)N(H)CH₃ H H I-134 O NH CH CH₃ H

H H I-135 O NH CH CH₃ H C(O)N(H)Ph H H I-136 O NH CH CH₃ pyrrolidin-1-ylC(O)NH₂ H H I-137 O NH CH CH₃ H C(O)N(H)CH₂CH₃ H H I-138 O NH CH CH₃ H

H H I-139 O NH CH CH₃ H

H H I-140 O NH CH CH₃ H

H H I-141 O NH CH CH₃ Cl C(O)NH₂ H H I-142 O NH CH CH₃ H

H H I-143 O NH CH CH₃ H

H H I-144 O NH CH CH₃ H

H H I-145 O NC(O)CH₂CH₃ CH CH₃ H C(O)NH₂ H H I-146 O NCH₂OP(O)(O- CH CH₃H C(O)NH₂ H H t-Bu)₂ I-147 O NCH₂OP(O)(OH)₂ CH CH₃ H C(O)NH₂ H H I-148 ONCH₂OP(O)(ONa)₂ CH CH₃ H C(O)NH₂ H H I-149 O NH CH CH₃ H

H H I-150 O NCH₂OP(O)(OH)₂ CH CH₃ H

H H I-151 O NCH₂OP(O)(ONa)₂ CH CH₃ H H H H I-152 O NCH₂OP(O)(O- t-Bu)₂CH CH₃ H

H H I-153 O NH CH CH₃ CF₃ Cl H H I-154 O NH CH CH₃ CF₃ CH₃ H H I-155 ONH CH CH₃ CF₃ SCH₃ H H I-156 O NH CH CH₃

C(O)NH₂ H H I-157 O NH CH CH₃

H H H I-158 O NH CH CH₃ CF₃ H H H I-159 O NH CH CH₃ CH₃ CO₂CH₃ H H I-160O NH CH CH₃ H CF₃ H H I-161 O NH CH CH₃ CF₃ OCF₃ H H I-162 O NH CH CH₃ FH CF₃ H I-163 O NH CH CH₃ OCF₃ F H H I-164 O NH CH CH₃ CF₃ CH₃ H H I-165O NH CH CH₃ CF₃ OCH₂CH₂OCH₃ H H I-166 O NH CH CH₃ CH₃ isopropyl H HI-167 O NH CH CH₃ Cl CF₃ H H I-168 O NH CH CH₃ CF₃ OCH₂CH₃ H H I-169 ONH CH CH₃ CF₃ H CF₃ H I-170 O NH CH CH₃ CH₃ CO₂H H H I-171 O NH CH CH₃CH₃ C(O)N(H)CH₂CH₃ H H I-172 O NH CH CH₃ H Cl H H I-173 O NH CH CH₃ Cl HH H I-174 O NH CH CH₃ H H H H I-175 O NH CH CH₃ Br H H H I-176 O NH CHCH₃ CH₃ Cl H CH₃ I-177 O NH CH CH₃ CF₃ N(H)C(O)CH₃ H H I-178 O NH CH CH₃CH₃ CH₃ H H I-179 O NH CH CH₃ CF₃ OCH₂-cyclohexyl H H I-180 O NH CH CH₃OCF₃ Cl H H I-181 O NH CH CH₃ OCH₃ Cl H H I-182 O NH CH CH₃ OCH₂CH₃ Cl HH I-183 O NH CH CH₃ OCH₃ F H H I-184 O NH CH CH₃ Cl H Cl H I-185 O NH CHCH₃ Br H Cl H I-186 O NH CH CH₃ Cl H F H I-187 O NH CH CH₃ Cl H CN HI-188 O NH CH CH₃ CF₃ Br H H I-189 O NH CH CH₃ Br H CF₃ H I-190 O NH CHCH₃ CH₃

H H I-191 O NH CH CH₃ Cl

H H I-192 O NH CH CH₃ H

H H I-193 O NH CH CH₃ OCH₃ F H F I-194 O NH CH CH₃ Cl OCH₂CH₃ H H I-195O NH CH CH₃ H OCH₂-cyclobutyl H H I-196 O NH CH CH₃ H OCH₂-isopropyl H HI-197 O NH CH CH₃ H OCH₂CH₂-isopropyl H H I-198 O NH CH CH₃ Cl CF₃ H HI-199 O NH CH CH₃ F H CH₃ H I-200 O NH CH CH₃ H F OCH₃ F I-201 O NH CHCH₃ H

H H I-202 O NH CH CH₃ H

H H I-203 O NH CH CH₃ H

H H I-204 O NH CH CH₃ H

H H I-205 O NH CH CH₃ H

H H I-206 O NH CH CH₃ H

H H I-207 O NH CH CH₃ H

H H I-208 O NH CH CH₃

H H H I-209 O NH CH CH₃

H H H I-210 O NH CH CH₃

H H H I-211 O NH CH CH₃

H H H I-212 O NH CH CH₃

H H H I-213 O NH CH CH₃

H H H I-214 O NH CH CH₃

H H H I-215 O NH CH CH₃

H H H I-216 O NH CH CH₃

H H H I-217 O NH CH CH₃

H H H I-218 O NH CH CH₃ CF₃

H H I-219 O NH CH CH₃ CF₃ C(O)N(H)Ph H H I-220 O NH CH CH₃ OCH₃

H H I-221 O NH CH CH₃ OCH₃ C(O)N(H)Ph H H I-222 O NH CH CH₃ CF₃ CO₂H H HI-223 O NH CH CH₃ CF₃

H H I-224 O NH CH CH₃ OCH₂CH(CH₃)₂ H CF₃ H I-225 O NH CH CH₃OCH₂-cyclopropyl H CF₃ H I-226 O NH CH CH₃ O-cyclobutyl H CF₃ H I-227 ONH CH CH₃ OCH₂-cyclobutyl H CF₃ H I-228 O NH CH CH₃ OCD₃ H CF₃ H I-229 ONH CH CH₃ C(O)CH₃ H OCH₃ H I-230 O NH CH CH₃ Cl F CF₃ H I-231 O NH CHCH₃

H OCH₃ H I-232 O NH CH CH₃

H OCH₃ H I-233 O NH CH CH₃

H OCH₃ H I-234 O NH CH CH₃

H OCH₃ H I-235 O NH CH CH₃

H OCH₃ H I-236 O NH CH CH₃

H OCH₃ H I-237 O NH CH CH₃ CH₃ H CF₂H H I-238 O NH CH CH₃ CH₃ H CH₂F HI-239 O NH CH CH₃ S(O)₂CH₃ CH₃ H H I-240 O NH CH CH₃ morpholin-4-yl H FH I-241 O NH CH CH₃

H F H I-242 O NH CH CH₃ S(O)₂CH₃ F H H I-243 O NH CCH₃ CH₃ S(O)₂NH₂ H HH I-244 O NH CCH₃ CH₃ S(O)₂NH₂ H H H I-245 O NH CCH₃ CH₃ S(O)₂NH₂ F H HI-246 O NH CH CH₃

H H H I-247 O NH CH CH₃ H

H H I-248 O NH CF CH₃ S(O)₂NH₂ H H H I-249 O NH CF CH₃ S(O)₂CH₃ H H HI-250 O NH CF CH₃ S(O)₂CH₃ F H H I-251 O NH CF CH₃ OCH₃ H CF₃ H I-252 ONH CH CH₃ C(O)N(CH₃)₂ H OCH₃ H I-253 O NH CH CH₃

H OCH₃ H I-254 O NH CH CH₃

H OCH₃ H I-255 O NH CH CH₃

H OCH₃ H I-256 O NH CH CH₃

H H H I-257 O NH CH CH₃ H

H H I-258 O NH CH CH₃ CH₃ OCH₃ H H I-259 O NH CH CH₃ OCH₃ H CH₃ H I-260O NH CH CH₃ C(O)N(CH₃)₂ OCH₃ H H I-261 O NH CH CH₃

OCH₃ H H I-262 O NH CH CH₃

OCH₃ H H I-263 O NH CH CH₃

OCH₃ H H I-264 O NH CH CH₃ CH₃ OCD₃ H H I-265 O NH CH CH₃ Cl OCH₃ CH₃ HI-266 O NH CH CH₃ OCD₃ H CH₃ H I-267 O NH CH CH₃ OCH₃ C(O)N(CH₃)₂ H HI-268 O NH CH CH₃ OCH₃

H H I-269 O NH CH CH₃ OCH₃

H H I-270 O NH CH CH₃ OCH₃

H H I-271 O NH CH CH₃ CF₂H OCH₃ H H I-272 O NH CH CH₃ H OCH₃ H H I-273 ONH CH CH₃ OCH₃ H CF₂H H I-274 O NH CH CH₃ OCH₃ H CH₂F H I-275 O NH CHCH₃ F

H H I-276 O NH CH CH₃ CF₃

H H I-277 O NH CH CH₃ Cl

H H I-278 O NH CH CH₃ Cl

H H I-279 O NH CH CH₃ H

H H I-280 O NH CH CH₃ OCH₃ H OCH₃ H I-281 O NH CH CH₃ F

H H I-282 O NH CH CH₃ F

F H I-283 O NH CH CH₃

Cl H H I-284 O NH CH CH₃

Cl H H I-285 O NH CH CH₃

CF₃ H H I-286 O NH CH CH₃ oxazol-5-yl H H H I-287 O NH CH CH₃ Br H H HI-288 O NH CH CH₃ H Br H H I-289 O NH CH CH₃ pyridin-4-yl H H H I-290 ONH CH CH₃ pyridin-3-yl H H H I-291 O NH CH CH₃ H pyridin-3-yl H H I-292O NH CH CH₃ OCH₂CH₂OCH₃ OCH₃ H H I-293 O NH CH CH₃

OCH₃ H H I-294 O NH CH CH₃ CN F H H I-295 O NH CH CH₃ CN pyrrol-1-yl H HI-296 O NH CH CH₃ OCH₃ H CF₃ H I-297 O NH CH CH₃ CF₃ OCH₃ H H I-298 O NHCH CH₃

OCH₃ H H I-299 O NH CH CH₃

OCH₃ H H I-300 O NH CH CH₃

OCH₃ H H I-301 O NH CH CH₃ CF₃ H CF₃ H I-302 O NH CH CH₃ CH₃ H CH₃ HI-303 O NH CH CH₃ CF₃ CN H H I-304 O NH CH CH₃ CH(OH)CF₃ H H H I-305 ONH CH CH₃ OCH₂CO₂CH₃ H H H I-306 O NH CH CH₃

H H H I-307 O NH CH CH₃ H OCH₂C(O)NH₂ H H I-308 O NH CH CH₃ H N(H)C(O)PhH H I-309 O NH CH CH₃ H N(CH₃)C(O)CH₃ H H I-310 O NH CH CH₃ CNpyrrolidin-1-yl H H I-311 O NH CH CH₃ H OCF₂H H H I-312 O NH CH CH₃OCF₂H H H H I-313 O NH CH CH₃ OCH₂CH₃ OCF₂H H H I-314 O NH CH CH₃ ClOCF₂H H H I-315 O NH CH CH₃

H H H I-316 O NH CH CH₃ C(O)NH₂

H H I-317 O NH CH CH₃ H

H H I-318 O NH CH CH₃ H

H H I-319 O NH CH CH₃ OCH₂C(O)NH₂ H H H I-320 O NH CH CH₃

H H H I-321 O NH CH CH₃

H H H I-322 O NH CH CH₃ H

H H I-323 O NH CH CH₃ C(O)NH₂

H H I-324 O NH CH CH₃ H OC(CH₃)₂C(O)NH₂ H H I-325 O NH CH CH₃ H H

CH₃ I-326 O NH CH CH₃ OCH₂C(O)N(CH₃)₂ H H H I-327 O NH CH CH₃ CNmorpholin-4-yl H H I-328 O NH CH CH₃ H H OCH₃ CH₃ I-329 O NH CH CH₃ Clpyridin-4-yl H H I-330 O NH CH CH₃ CF₃ pyridin-4-yl H H I-331 O NH CHCH₃ CH₂OH

H H I-332 O NH CH CH₃ H piperazin-1-yl H H I-333 O NH CH CH₃ H

H H I-334 O NH CH CH₃ H OC(CH₃)₂CN H H I-335 O NH CH CH₃ OC(CH₃)₂C(O)NH₂H H H I-336 O NH CH CH₃ OCH₃ CO₂CH₃ H H I-337 O NH CH CH₃ OCH₃ H H HI-338 O NH CH CH₃ H morpholin-4-yl H H I-339 O NH CH CH₃ CNthiomorpholin-4-yl H H I-340 O NH CH CH₃ OCH₃

H H I-341 O NH CH CH₃ CN

H H I-342 O NH CH CH₃ OC(CH₃)₂CN H H H I-343 O NH CH CH₃ H

H H I-344 O NH CH CH₃ H

H H I-345 O NH CH CH₃

H H H I-346 O NH CH CH₃

H H H I-347 O NH CH CH₃ F OCF₂H H H I-348 O NH CH CH₃ Cl OCF₂H Cl HI-349 O NH CH CH₃ OCH₃ F H H I-350 O NH CH CH₃ F OCH₃ H H I-351 O NH CHCH₃ OCH₃ CH₃ H H I-352 O NH CH CH₃ F H OCH₃ H I-353 O NH CH CH₃ CF₃ HOCF₂H H I-354 O NH CH CH₃ OCH₃ CF₃ H H I-355 O NH CH CH₃ t-butyl Ht-butyl H I-356 O NCH₂OP(O)(O- CH CH₃ OCH₃ H CF₃ H t-Bu)₂ I-357 ONCH₂OP(O)(OH)₂ CH CH₃ OCH₃ H CF₃ H I-358 O NCH₂OP(O)(ONa)₂ CH CH₃ OCH₃ HCF₃ H I-359 O NH CH CH₃ F H F H I-360 O NH CH CH₃ F H CF₃ H I-361 O NHCH CH₃ CF₃ F H H I-362 O NH CH CH₃ CH₃ F H H I-363 O NH CH CH₃ F CH₃ H HI-364 O NH CH CH₃ Cl CH₃ H H I-365 O NH CH CH₃ CH₃ CH₃ CH₃ H I-366 O NHCH CH₃ Cl OCF₃ H H I-367 O NH CH CH₃ H SCF₃ H H I-368 O NH CH CH₃ F H HH I-369 O NH CH CH₃ CH₃ OCH₃ CH₃ H I-370 O NH CH CH₃ C(O)NH₂ H CF₃ HI-371 O NH CH CH₃ isopropyl OCH₃ isopropyl H I-372 O NH CH CH₃O-isopropyl H CF₃ H I-373 O NH CH CH₃ CN OCH₃ H H I-374 O NH CH CH₃ CH₃F CH₃ H I-375 O NH CH CH₃ OCF₃ F H H I-376 O NH CH CH₃ F OCF₃ H H I-377O NH CH CH₃ OCF₃ Cl H H I-378 O NH CH CH₃ Cl H OCF₃ H I-379 O NH CH CH₃CH₃ H OCF₃ H I-380 O NH CH CH₃ OCH₃ CN H H I-381 O NH CH CH₃ F OCH₃ F HI-382 O NH CH CH₃ H

H H I-383 O NH CH CH₃ CN Cl CH₂CH₃ H I-384 O NH CH CH₃ OCH₂CH₂OCH₃ H CF₃H I-385 O NH CH CH₃ CH₃ OCF₂H CH₃ H I-386 O NH CH CH₃ OC(CH₃)₂C(O)NH₂ FH H I-387 O NH CH CH₃ CH₃ OCF₂H H H I-388 O NH CH CH₃ F OCF₂H F H I-389O NH CH CH₃ CH₃ OC(CH₃)₂C(O)NH₂ CH₃ H I-390 O NH CH CH₃ OCF₂H CH₃ H HI-391 O NH CH CH₃ CH₃ OC(CH₃)₂C(O)NH₂ H H I-392 O NH CH CH₃OC(CH₃)₂C(O)NH₂ CH₃ H H I-393 O NH CH CH₃ CF₃ H OCH₃ H I-394 O NH CH CH₃CH₃ Cl CH₃ H I-395 O NH CH CH₃ F OC(CH₃)₂C(O)NH₂ F H I-396 O NH CH CH₃CH(OCH₃)CF₃ H H H I-397 O NH CH CH₃ OC(CH₃)₂CN CH₃ H H I-398 O NH CH CH₃F F H H I-399 O NH CH CH₃ Cl F H H I-400 O NH CH CH₃ F Cl H H I-401 O NHCH CH₃ F H OCF₂H H I-402 O NH CH CH₃ OC(CH₃)₂C(O)NH₂ H F H I-403 O NH CHCH₃ CH₃ H H H I-404 O NH CH CH₃ CF₃

H H I-405 O NCH₂OP(O)(O- CH CH₃ CH₃ CH₃ CH₃ H t-Bu)₂ I-406 ONCH₂OP(O)(OH)₂ CH CH₃ CH₃ CH₃ CH₃ H I-407 O NCH₂OP(O)(ONa)₂ CH CH₃ CH₃CH₃ CH₃ H I-408 O NH CH CH₃ F F F H I-409 O NH CH CH₃ OCH₃ F CF₃ H I-410O NH CH CH₃ OCH₃ F CF₃ H I-411 O NH CH CH₃ OCH₃ F CF₃ H I-412 O NH CHCH₃ OCH₃ F CF₃ H I-413 O NH CH CH₃ OCH₃ F CF₃ H I-414 O NH CH CH₃ OCH₃ FCF₃ H I-415 O NH CH CH₃ F CF₃ F H I-416 O NH CH CH₃ OC(CH₃)₂CN H F HI-417 O NH CH CH₃ OC(CH₃)₂CN F H H I-418 O NH CH CH₃ OCF₂H Cl H H I-419O NH CH CH₃ H isopropyl H H I-420 O NH CH CH₃ H t-butyl H H I-421 O NHCH CH₃ H CH₃ H H I-422 O NH CH CH₃ CH₂O-isopropyl OCH₃ H H I-423 O NH CHCH₃

H OCH₃ H I-424 O NH CH CH₃ H OH Cl H I-425 O NH CH CH₃ H OH H H I-426 ONH CH CH₃ H

H H I-427 O NH CCH₃ CH₃ OCH₃ H CF₃ H I-428 O NH CCH₃ CH₃ OCH₃ H CH₃ HI-429 O NH CCH₃ CH₃ H OCH₃ CH₃ H I-430 O NH CF CH₃ OCH₃ H CH₃ H I-431 ONH CF CH₃ H OCH₃ CH₃ H I-432 O NH CH CH₃ OCH₃ F CH₃ H I-433 O NH CH CH₃H OCF₂H CH₂F H I-434 O NH CH CH₃ H CN OCF₂H H I-435 O NH CH CH₃ H FOCF₂H H I-436 O NH CH CH₃ CH₃ CH₃ CH₃ H I-437 O NH CH CH₃ CH₃ F CH₃ HI-438 O NH CH CH₃ H CH₃ CF₂H H I-439 O NH CH CH₃ H CH₃ CH₂F H I-440 O NHCH CH₃ OCH₃ H CF₃ H I-441 O NH CH CH₃ H OCD₃ CF₃ H I-442 O NH CH CH₃ HOCF₂H CF₂H H I-443 O NH CH CH₃ pyridin-4-yl CH₃ H H I-444 O NH CH CH₃pyridin-3-yl CH₃ H H I-445 O NH CH CH₃ C(O)CH₃ H CF₃ H I-446 O NH CH CH₃

H CF₃ H I-447 O NH CH CH₃ H OCD₃ H H I-448 O NH CH CH₃ H OCD₃ Cl H I-449O NH CH CH₃ H

H H I-450 O NCH₂OP(O)(O- CH CH₃ CH₃ F CH₃ H t-Bu)₂ I-451 ONCH₂OP(O)(ONa)₂ CH CH₃ CH₃ F CH₃ H I-452 O NH CH CH₃ OCH₃ OCH₃ CH₃ HI-453 O NH CCH₃ CH₃ OCH₃ OCH₃ CH₃ H I-454 O NH CF CH₃ OCH₃ OCH₃ CH₃ HI-455 O NH CH CH₃ H

Cl H I-456 O NH CH CH₃ H F H F I-457 O NH CH CH₃

H CF₃ H I-458 O NH CH CH₃ OCH₃ OCH₃ Cl H I-459 O NH CH CH₃ CH₃

CH₃ H I-460 O NH CH CH₃

H CF₃ H I-461 O NH CH CH₃

H CF₃ H I-462 O NH CH CH₃

H CF₃ H I-463 O NH CH CH₃

H CF₃ H I-464 O NH CH CH₃

H CF₃ H I-465 O NH CH CH₃

H CF₃ H I-466 O NH CH CH₃ F H H F I-467 O NH CH CH₃ H H F F I-468 O NHCH CH₃ H H H F I-469 O NH CH CH₃

H CF₃ H I-470 O NH CH CH₃ H F H H I-471 O NH CH CH₃ pyridin-4-yl F H HI-472 O NH CH CH₃ pyridin-3-yl F H H I-473 O NH CH CH₃

H CF₃ H I-474 O NH CCH₃ CH₃ CH₃ H CH₃ H I-475 O NH CCH₃ CH₃ CH₃ CH₃ CH₃H I-476 O NH CCH₃ CH₃ CH₃ F CH₃ H I-477 O NH CH CH₃ F F F F I-478 O NHCH CH₃ CN H OCF₂H H I-479 O NH CH CH₃ CH₃ H CF₃ H I-480 O NH CH CH₃ F HF F I-481 O NH CH CH₃ F F H F I-482 O NH CH CH₃ CH₃ pyridin-4-yl H HI-483 O NH CH CH₃ CH₃ pyridin-3-yl H H I-484 O NH CH CH₃ F pyridin-4-ylH H I-485 O NH CH CH₃ CF₃ OCH₃ OCH₃ H I-486 O NH CH CH₃ pyridin-4-ylOCH₃ H H I-487 O NH CH CH₃ pyridin-3-yl OCH₃ H H I-488 O NH CF CH₃ CH₃ HCH₃ H I-489 O NH CF CH₃ CH₃ CH₃ CH₃ H I-490 O NH CF CH₃ CH₃ F CH₃ HI-491 O NH CCH₃ CH₃ OCH₃ F CH₃ H I-492 O NH CF CH₃ OCH₃ F CH₃ H I-493 ONH CH CH₃ H CH₃ CH₃ F I-494 O NH CH CH₃ OCH₃ pyridin-4-yl H H I-495 O NHCH CH₃ OCF₂H H Cl H I-496 O NH CH CH₃ H OCH₃ Cl H I-497 O NH CH CH₃ CF₃H Cl H I-498 O NH CH CH₃ CF₃ H H OCH₃ I-499 O NH CH CH₃ H H H CH₃ I-500O NH CH CH₃ H H CH₃ CH₃ I-501 O NH CH CH₃ CH₃ H H CH₃ I-502 O NH CH CH₃H H H Et I-503 O NH CH CH₃ CH₂CH₃ H H H I-504 O NH CH CH₃ H CH₂CH₃ H HI-505 O NH CH CH₃ F pyridin-3-yl H H I-506 O NH CH CH₃ OCH₃ pyridin-3-ylH H I-507 O NH CCH₃ CH₃ H F OCH₃ F I-508 O NH CF CH₃ H F OCH₃ F I-509 ONH CH CH₃ H 6-Cl-pyridin-3-yl H H I-510 O NH CH CH₃ H

H H I-511 O NH CH CH₃ H

H H I-512 O NH CH CH₃ H

H H I-513 O NH CH CH₃ H H CH₃ F I-514 O NH CH CH₃ H CH₃ H F I-515 O NHCH CH₃ CH₃ H H F I-516 O NH CH CH₃ OCF₂H H CH₃ H I-517 O NCH₂OP(O)(OH)₂CH CH₃ CH₃ CH₃ CH₃ H I-518 O NH CH CH₃ H H CF₃ CH₃ I-519 O NH CH CH₃C(O)CH₃ H H F I-520 O NH CH CH₃ H H H Cl I-521 O NH CH CH₃ CH₃ H H ClI-522 O NH CCl CH₃ CH₃ CH₃ CH₃ Cl I-523 O NH CH CH₃

H H F I-524 O NCH₂OP(O)(O- CCl CH₃ CH₃ CH₃ CH₃ H t-Bu)₂ I-525 ONCH₂OP(O)(OH)₂ CCl CH₃ CH₃ CH₃ CH₃ H I-526 O NCH₂OP(O)(OH)₂ CH CH₃ CH₃CH₃ CH₃ H I-527 O NH CH CH₃ CH₃ I CH₃ H I-528 O NCH₂OP(O)(ONa)₂ CCl CH₃CH₃ CH₃ CH₃ H I-529 O NH CH CH₃ OCH₃ CH₃ OCH₃ H I-530 O NH CH CH₃ CH₃CH₃ H F I-531 O NCH₂OP(O)(OH)₂ CH CH₃ CH₃ CH₃ CH₃ H I-532 O NH CH CH₃ HCH₃ CF₃ F I-533 O NH CH CH₃ OCH₃ H H F I-534 O NH CH CH₃ CH₃ CH₃ CH₃ FI-535 O NH CH CH₃ OCH₃ CH₃ CH₃ H I-536 O NCH₂OP(O)(OH)₂ CCH₃ CH₃ OCH₃ HCH₃ H I-537 O NH CH CH₃ CH₃ CH₃ F H I-538 O NCH₂OP(O)(ONa)₂ CH CH₃ OCH₃F CH₃ H

TABLE II

Cpd X Y Z¹ R⁵ R^(2a) R^(2b) R^(2c) R^(2d) II-1  O NH CH CH₃ H H —N(CH₃)₂H II-2  O NH CH CH₃ H H

H II-3  O NH CH CH₃ H H 1-methyl-1,4-diazepan-4-yl H II-4  ON-(n-propyl) CH CH₃ H H 1-methylpiperazin-4-yl H II-5  O N-(n-propyl) CHCH₃ H H

H II-6  O NH CH CH₃ H H 4-methylpiperidin-1-yl H II-7  O N-(isopropyl)CH CH₃ H H 1-methylpiperazin-4-yl H II-8  O NH CH CH₃ H H

H II-9  O NH CH CH₃ H H

H II-10  O NH CH CH₃ H H piperazin-1-yl H II-11  O NH CH CH₃ H H

H II-12  O NH CH CH₃ H H

H II-13  O NH CH CH₃ H H 1-methylpiperazin-4-yl H II-14  O NH CH F H H1-methylpiperazin-4-yl H II-15  NH NH CH CH₃ H H 1-methylpiperazin-4-ylH II-16  NH NH CH F H H 1-methylpiperazin-4-yl H II-17  O NH CH CH₃ H Hmorpholin-4-yl H II-18  O NH CH F H H morpholin-4-yl H II-19  NH NH CH FH H morpholin-4-yl H II-20  NCH₃ NCH₃ CH CH₃ H H 1-methylpiperazin-4-ylH II-21  NCH₃ NCH₃ CH F H H 1-methylpiperazin-4-yl H II-22  O NCH₃ CHCH₃ H H 1-methylpiperazin-4-yl H II-23  NCH₃ O CH CH₃ H H1-methylpiperazin-4-yl H II-24  O NCH₃ CH F H H 1-methylpiperazin-4-yl HII-25  NH O CH CH₃ H H 1-methylpiperazin-4-yl H II-26  O NH CH CH₃ H CH₃1-methylpiperazin-4-yl H II-27  NH NH CH CH₃ H CH₃1-methylpiperazin-4-yl H II-28  O NH CH CH₃ H CH₃

H II-29  O NH CH F H CH₃

H II-30  O NH CH F H CH₃ 1-methylpiperazin-4-yl H II-31  O NH CH CH₃ H H

H II-32  O NH CH CH₃ H H

H II-33  O NH CH F H H

H II-34  O NH CH F H H

H II-35  O NH CH CH₃ H H —N(H)-1-methylpiperidin-4-yl H II-36  O NH CHCH₃ H H —N(H)-piperidin-4-yl H II-37  O NH CH CH₃ H H

H II-38  O NH CH CH₃ H H

H II-39  O NH CH CH₃ H CF₃ 1-methylpiperazin-4-yl H II-40  O NH CH CH₃ HF

H II-41  O NH CH CH₃ H H

H II-42  O NH CH CH₃ H H H H II-43  O NH CH CH₃ H H S(O)₂CH₃ H II-44  ONH CH CH₃ H H

H II-45  O NH CH CH₃ H H —C(O)-piperazin-l-yl H II-46  O NH CH CH₃ H H

H II-47  O NH CH CH₃ H H

H II-48  O NH CH CH₃ H F

H II-49  O NH CH CH₃ H F

H II-50  O NH CH CH₃ H F

H II-51  O NH CH CH₃ H F

H II-52  O NH CH CH₃ H F

H II-53  O NH CH CH₃ H F

H II-54  O NH CH CH₃ H F

H II-55  O NH CH CH₃ H H

H II-56  O NH CH CH₃ H H

H II-57  O NH CH CH₃ H H

H II-58  O NH CH CH₃ H H

H II-59  O NH CH CH₃ H H 4,4-difluoropiperidin-l-yl H II-60  O NH CH CH₃H H 4,4-dimethylpiperidin-1-yl H II-61  O NH CH CH₃ H CH₃

H II-62  O NH CH CH₃ H CH₃

H II-63  O NH CH CH₃ H CH₃

H II-64  O NH CH CH₃ H CH₃

H II-65  O NH CH CH₃ H CH₃

H II-66  O NH CH CH₃ H CH₃

H II-67  O NH CH CH₃ H CH₃

H II-68  O NH CH CH₃ H CH₃

H II-69  O NH CH CH₃ H CH₃

H II-70  O NH CH CH₃ H H

H II-71  O NH CH CH₃ H H pyrrolidin-l-yl H II-72  O NH CCH₃ CH₃ H H1-methylpiperazin-4-yl H II-73  O NH CCH₃ CH₃ H H morpholin-4-yl HII-74  O NH CH CH₃ H H —N(H)CH₂-cyclopropyl H II-75  O NH CF CH₃ H H1-methylpiperazin-4-yl H II-76  O NH CF CH₃ H H morpholin-4-yl H II-77 O NH CH CH₃ H Br H H II-78  O NH CH CH₃ H H —N(H)S(O)₂CH₃ H II-79  ONCH₃ CH CH₃ H H —N(H)S(O)₂CH₃ H II-80  O NH CH CH₃ H H

H II-81  O NH CH CH₃ H H

H II-82  O NH CH CH₃ H H

H II-83  O NH CH CH₃ H H

H II-84  O NH CH CH₃ H H

H II-85  O NH CH CF₃ H H 1-methylpiperazin-4-yl H II-86  O NH CH CH₃ H H

H II-87  O NH CH CH₃ H H

H II-88  O NH CH CH₃ H H

H II-89  O NH CH CH₃ H H

H II-90  O NH CH CH₃ H H

H II-91  O NH CH CH₃ H H

H II-92  O NH CH CH₃ H H

H II-93  O NH CH CH₃ H H

H II-94  O NH CH CH₃ H H

H II-95  O NH CH CH₃ H H

H II-96  O NH CH CH₃ H H

H II-97  O NH CH CH₃ H H

H II-98  O NH CH CH₃ H H

H II-99  O NH CH CH₃ H H

H II-100 O NH CH CH₃ H H

H II-101 O NH CH CH₃ H H

H II-102 O NH CH CH₃ H H

H II-103 O NH CH CH₃ H H

H II-104 O NH CH CH₃ H H

H II-105 O NH CH CH₃ H H

H II-106 O NH CH CH₃ H H

H II-107 O NH CH CH₃ H H

H II-108 O NH CH CH₃ H H

H II-109 O NH CH CH₃ H CF₃

H II-110 O NH CH CH₃ H CF₃ 1-ethylpiperazin-4-yl H II-111 O NH CH CH₃ HF 1-methylpiperazin-4-yl H II-112 O NH CH CH₃ H F

H II-113 O NH CH CH₃ H F

H II-114 O NH CH CH₃ H F 1-ethylpiperazin-4-yl H II-115 O NH CH CH₃ H CN

H II-116 O NH CH CH₃ H Cl 1-methylpiperazin-4-yl H II-117 O NH CH CH₃ HH

H II-118 O NH CH CH₃ H Cl

H II-119 O NH CH CH₃ H CF₃

H II-120 O NH CH CH₃ H H

H II-121 O NH CH CH₃ H H

H II-122 O NH CH CH₃ H Cl

H II-123 O NH CH CH₃ H H —OCH₃ H II-124 O NH CH CH₃ H CF₃

H II-125 O NH CH CH₃ H F

H II-126 O NH CH CH₃ H H

H II-127 O NH CH CH₃ H H

H II-128 O NH CH CH₃ H H

H II-129 O NH CH CH₃ H H

H II-130 O NH CH CH₃ H H

H II-131 O NH CH CH₃ H H

H II-132 O NH CH CH₃ H H

H II-133 O NH CH CH₃ H H

H II-134 O NH CH CH₃ H H

H II-135 O NH CH CH₃ H H

H II-136 O NH CH CH₃ H H 1-isopropylpiperazin-4-yl H II-137 O NH CH CH₃H H

H II-138 O NH CH CH₃ H H

H II-139 O NH CH CH₃ H H

H II-140 O NH CH CH₃ H OCH₃ OCH₃ H II-141 O NH CH CH₃ H OCH₃ OCH₃ HII-142 O NH CH CH₃ H H OCH₂CH₂OH H II-143 O NH CH CH₃ CH₃ H1-methylpiperazin-4-yl H II-144 O NH CH CH₃ H H OCH(CH₃)₂ H II-145 O NHCH CH₃ H H OCH₂CH₂OCH₃ H II-146 O NH CH CH₃ H H OC(CH₃)₂C(O)NH₂ H II-147O NH CH CH₃ H CF₃ OCH₃ H II-148 O NH CH CH₃ H H OCH₂CH₂CH₂OH H II-149 ONH CH CH₃ H H OCH₂CH₂CH₂OCH₃ H II-150 O NH CH CH₃ H Cl

H II-151 O NH CH CH₃ H H

H II-152 O NH CH CH₃ H OCH₃ H H II-153 O NH CH CH₃ H CH₃ CH₃ H

TABLE III

Cpd Y R³ R^(a) or R^(b) III-1  NH H H III-2  NH H OH III-3  NH HCO₂-t-Bu III-4  NH H CH₃ III-5  NH H CH₂CH₃ III-6  NH H n-propyl III-7 NH H CH₂-cyclopropyl III-8  NH H CH₂-isopropyl III-9  NH HCH₂-CH₂-isopropyl III-10 NH H CH₂-cyclopentyl III-11 NH HCH₂-(bicyclo[2.2.1] hept-5-en-2-yl) III-12 NH H C(O)CH₃ III-13NC(O)-t-Bu C(O)-t-Bu C(O)-t-Bu III-14 NH H S(O)₂CH₃

TABLE IV

Cpd

IV-1 

IV-2 

IV-3 

IV-4 

IV-5 

IV-6 

IV-7 

IV-8 

IV-9 

IV-10

IV-11

IV-12

IV-13

IV-14

IV-15

IV-16

IV-17

IV-18

IV-19

IV-20

IV-21

IV-22

IV-23

IV-24

IV-25

IV-26

IV-27

IV-28

IV-29

IV-30

IV-31

IV-32

IV-33

IV-34

IV-35

IV-36

IV-37

IV-38

IV-39

IV-40

IV-41

IV-42

IV-43

IV-44

IV-45

IV-46

IV-47

IV-48

IV-49

IV-50

IV-51

IV-52

IV-53

IV-54

IV-55

IV-56

IV-57

IV-58

IV-59

IV-60

IV-61

IV-62

IV-63

IV-64

Prodrugs

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein can include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the 2,4-pyrimidinediamine compoundsdescribed in this invention include promoieties that are hydrolyzable orotherwise cleavable under conditions of use. For example, ester groupscommonly undergo acid-catalyzed hydrolysis to yield the parentcarboxylic acid when exposed to the acidic conditions of the stomach orbase-catalyzed hydrolysis when exposed to the basic conditions of theintestine or blood. Thus, when administered to a subject orally,2,4-pyrimidinediamine compounds that include ester moieties can beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical andcan be caused, for example, by hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-pyrimidinediamine can employ progroupsincluding such esters. Alternatively, the progroups can be designed tometabolize in the presence of enzymes such as esterases, amidases,lipolases, and phosphatases, including ATPases and kinase, etc.Progroups including linkages capable of metabolizing in vivo are wellknown and include, by way of example and not limitation, ethers,thioethers, silylethers, silylthioethers, esters, thioesters,carbonates, thiocarbonates, carbamates, thiocarbamates, ureas,thioureas, and carboxamides. In some instances, a “precursor” group thatis oxidized by oxidative enzymes such as, for example, cytochrome P₄₅₀of the liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety can be masked with aprogroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that can be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), and carboxyls. Awide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in active 2,4-pyrimidinediaminecompounds to yield prodrugs are well-known in the art. For example, ahydroxyl functional group can be masked as a sulfonate, ester, orcarbonate promoiety, which can be hydrolyzed in vivo to provide thehydroxyl group. An amino functional group can be masked as an amide,carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl promoiety,which can be hydrolyzed in vivo to provide the amino group. A carboxylgroup can be masked as an ester (including silyl esters and thioesters),amide, or hydrazide promoiety, which can be hydrolyzed in vivo toprovide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art. All of these progroups, alone or in combinations, canbe included in the prodrugs.

In some embodiments of the 2,4-pyrimidinediamine compounds and methodsof using the compounds, the progroup(s) can be attached to any availableprimary or secondary amine, including, for example, the N2 nitrogen atomof the 2,4-pyrimidinediamine, the N4 nitrogen atom of the2,4-pyrimidinediamine, and/or a primary or secondary nitrogen atomincluded in a substituent on the 2,4-pyrimidinediamine.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample, under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a biologically active group, e.g., the2,4-pyrimidinediamines as described herein. Thus, skilled artisans willappreciate that the progroup can include virtually any known orlater-discovered hydroxyl, amine or thiol protecting group. Non-limitingexamples of suitable protecting groups can be found, for example, inProtective Groups in Organic Synthesis, Greene & Wuts, 2^(nd) Ed., JohnWiley & Sons, New York, 1991 (especially pages 10-142 (alcohols, 277-308(thiols) and 309-405 (amines) the disclosure of which is incorporatedherein by reference, herein referred to as “Green & Wuts”).

A particularly useful progroup employed in exemplary disclosed compoundsis —CH₂OP(OH)₂ as well as esters, mixed acid esters and salts thereof.In some embodiments, the —CH₂OP(OH)₂ progroup is attached via a nitrogenatom, annular or not, of the parent molecule. There can be more than onesuch progroup. Thus, one embodiment is a compound of formula I,

or solvate thereof, where A, X, Y, Z¹, Z², R², R³, R⁴, R⁵ and p are asdescribed herein above, and at least one of R¹ (when present), R³ and R⁴is R⁵⁰; where R⁵⁰ is —CH₂OP(O)(OR¹¹)₂; each R¹¹ is independently foreach occurrence H, C₁₋₆alkyl or monovalent cationic group, or two R¹¹,together with the atoms to which they are attached, form a 4-8 memberedcyclic phosphate group

where each R⁵⁵ is independently for each occurrence H, optionallysubstituted C₁₋₆alkyl, optionally substituted 3-8 memberedheteroalicyclyl, optionally substituted C₆₋₁₄aryl, optionallysubstituted C₇₋₂₀arylalkyl, optionally substituted 5-14 memberedheteroaryl or optionally substituted 6-15 membered heteroarylalkyl; z is0, 1, 2 or 3; or two R¹¹ together represent a divalent organic orinorganic cationic group, wherein exemplary inorganic divalent cationicgroups include those selected from Ba²⁺, Bi²⁺, Ca²⁺, Cu²⁺, Mg²⁺, Ni²⁺,Sr²⁺ and Zn²⁺.

Another embodiment of the presently disclosed compounds includescompounds of formula III

or solvate thereof, where A, Z¹, Z², R², R³, R⁴, R⁵ and p are asdescribed herein above, and at least one of R¹, R³ and R⁴ is R⁵⁰; whereR⁵⁰ is —CH₂OP(O)(OR¹¹)₂; each R¹¹ is independently for each occurrenceH, C₁₋₆alkyl or a monovalent cationic group, or two R¹¹, together withthe atoms to which they are attached, form a 5 or 6-membered cyclicphosphate group, where —CH₂OP(O)(OR¹¹)₂ is

or two R¹¹ together represent a pharmaceutically acceptable divalentcationic group, by way of example including those selected from Ca²⁺,Mg²⁺ and Zn²⁺.

Another embodiment is a compound of formula IV

or solvate thereof, where A, Z¹, Z², R², R⁵ and p are as describedherein above, and R⁵⁰ is —CH₂OP(O)(OR¹¹)₂; each R¹¹ is independently foreach occurrence H, C₁₋₆alkyl, Li⁺, K⁺, HOCH₂CH₂N(CH₃)₃ ⁺, Na⁺ or NH₄ ⁺;or two R¹¹ together represent a divalent cationic group selected fromCa²⁺, Mg²⁺ and Zn²⁺.

Another embodiment is a compound of formula V

or solvate thereof, where A, Z¹, Z², R², R⁵ and p are as describedherein above, and each R¹¹ is independently for each occurrence H,t-butyl, Li⁺, HOCH₂CH₂N(CH₃)₃ ⁺, K⁺, Na⁺ or NH₄ ⁺; or two R¹¹ togetherrepresent a divalent cationic group selected from Ca²⁺, Mg²⁺ and Zn²⁺.

While not intending to be bound by any particular theory of operation,it is believed that progroups —CH₂OP(O)(OR¹¹)₂, e.g. according toformula V, metabolize to active compounds via the correspondinghydroxymethylamine intermediate illustrated below:

Such hydroxymethylamine compounds, although typically isolable undercontrolled conditions, are known to be unstable under physiologicalconditions and various pH ranges where they hydrolyze in vivo to yieldformaldehyde and the active drug substance. Based on this observation,compounds of the invention include hydroxymethyl progroups that can bemetabolized in vivo, for example by the acidic conditions of the stomachand/or by enzymes present in the digestive tract or other organs and/ortissues or fluids with the body, to yield the active drug substance2,4-pyrimidinediamine.

Moreover, it is expected that the amino and thio analogs of thesehydroxymethylamines, will be similarly unstable at physiologicalconditions and also hydrolyze in vivo to the active 2,4-pyrimdiendiaminedrug. Accordingly, compounds of the invention include thesecorresponding primary amino and thiol compounds. Also, the inventionincludes compounds in which the primary amine, thiol and hydroxy groupsare masked with “protecting” groups that are removed under physiologicalconditions of use to yield the corresponding hydroxymethyl, thiolmethyland aminomethyl compounds, that is, with these “protecting groups” thesecompounds will likewise make suitable prodrugs.

Suitability of any particular progroup for a desired mode ofadministration can be confirmed in biochemical assays. For example, if aprodrug is to be administered by injection into a particular tissue ororgan and the identities of the various enzyme(s) expressed in thetissue or organ are known, the particular prodrug can be tested formetabolism in biochemical assays with the isolated enzyme(s).Alternatively, the particular prodrug can be tested for metabolism tothe active 2,4-pyrimidinediamine compound with tissue and/or organextracts. Using tissue and/or organ extracts can be of particularconvenience when the identity(ies) of the enzymes expressed in thetarget tissues or organs are unknown or in instances when the isolatedenzymes are not conveniently available. Skilled artisans will be able toreadily select progroups having metabolic properties (such as kinetics)suitable for particular applications using such in vitro tests. Specificprodrugs could also be tested for suitable metabolism in vitro animalmodels.

Compounds of the invention bearing the —CH₂OP(O)(OR¹¹)₂ progroup can besynthesized, e.g., as depicted below for compounds of formula V.

Typically, the proton on the NH of the oxazolidinone ring can beselectively alkylated with the appropriate phosphonate reagent, where LGis a suitable leaving group to form compounds of the invention, in thiscase of formula V. Further description of how to make progroups offormula —CH₂OP(O)(OR¹¹)₂ as described herein is specifically taught inU.S. Pat. No. 7,449,458, entitled “Pyrimidinediamine Prodrugs and theirUses,” the disclosure of which is hereby incorporated by reference inits entirety.

One of ordinary skill in the art will appreciate that compounds of theinvention may exhibit the phenomena of tautomerism, conformationalisomerism, geometric isomerism, and/or optical isomerism. For example,the compounds and prodrugs of the invention can include one or morechiral centers and/or double bonds and as a consequence can exist asstereoisomers, such as double-bond isomers (such as, geometric isomers),enantiomers, diasteromers, and mixtures thereof, such as racemicmixtures. As another example, the compounds of the invention can existin several tautomeric forms, including the enol form, the keto form, andmixtures thereof. As the various compound names, formulae and compounddrawings within the specification and claims can represent only one ofthe possible tautomeric, conformational isomeric, optical isomeric, orgeometric isomeric forms, it would be understood that the inventionencompasses any tautomeric, conformational isomeric, optical isomeric,and/or geometric isomeric forms of the compounds described herein, aswell as mixtures of these various different isomeric forms. In cases oflimited rotation, e.g. around the 2,4-pryimidinediamine core structure,atropisomers are also possible and are also specifically included in thecompounds of the invention. It is intended that the compoundsencompassed herein are, with the exception of forms of isomerism,chemically stable and isolable.

As is understood by one of ordinary skill in the art, certain atomsoccur in more than one isotopic form. For example hydrogen occurs asprotium (¹H), deuterium (²H) and tritium (³H), and carbon occursnaturally as three different isotopes, ¹²C, ¹³C and ¹⁴C. Thus thepresently disclosed formulas include compounds having one or moredifferent isotopic forms of certain elements, including hydrogen andcarbon. In one embodiment of the disclosure, the presently disclosedcompounds are provided in isotopically enriched form. In particularexamples, compounds of formula I are enriched in deuterium relative toprotium.

Deuterium has a natural abundance of about 0.015%. Accordingly, forapproximately every 6,500 hydrogen atoms occurring in nature, there isone deuterium atom. Disclosed herein are compounds enriched in deuteriumat one or more positions. Thus, deuterium containing compounds of thedisclosure have deuterium at one or more positions (as the case may be)in an abundance of greater than 0.015%.

In one embodiment, a compound of formula (I), at a position designatedas having deuterium, has a minimum isotopic enrichment factor of atleast 2000 (30% deuterium incorporation) at each atom designated asdeuterium in the compound, or at least 3000 (45% deuteriumincorporation).

In other embodiments, a compound of formula (I) has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutical Compositions

Another embodiment is a pharmaceutical composition including a compoundas described in any of the embodiments above. Pharmaceuticalcompositions described herein can be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping, or lyophilization processes. Thecompositions can be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients, orauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically.

The 2,4-pyrimidinediamine compound can be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide, or pharmaceutically acceptable salt, as describedherein. Typically, such salts are more soluble in aqueous solutions thanthe corresponding free acids and bases, but salts having lowersolubility than the corresponding free acids and bases can also beformed.

One embodiment is a pharmaceutical formulation including a compound offormula I, as described herein, or a prodrug thereof, and at least onepharmaceutically acceptable excipient, diluent, preservative,stabilizer, or mixture thereof.

The compounds can be provided in a variety of formulations and dosages.The compounds can be provided in a pharmaceutically acceptable form,including where the compound can be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide, orpharmaceutically acceptable salt, as described herein. Typically, suchsalts are more soluble in aqueous solutions than the corresponding freeacids and bases, but salts having lower solubility than thecorresponding free acids and bases can also be formed. It is to beunderstood that reference to the compound, 2,4-pyrimidinediaminecompound, or “active” in discussions of formulations is also intended toinclude, where appropriate as known to those of skill in the art,formulation of the prodrugs of the 2,4-pyrimidinediamine compounds.

In one embodiment, the compounds are provided as non-toxicpharmaceutically acceptable salts, as noted previously. Suitablepharmaceutically acceptable salts of the compounds described hereininclude acid addition salts such as those formed with hydrochloric acid,fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid, or phosphoricacid. Salts of amine groups can also include quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl, or substituted alkyl moiety. Furthermore,where presently disclosed compounds carry an acidic moiety, suitablepharmaceutically acceptable salts thereof can include metal salts suchas alkali metal salts, e.g., sodium or potassium salts; and alkalineearth metal salts, e.g., calcium or magnesium salts.

The pharmaceutical compositions for the administration of the2,4-pyrimidinediamine compounds can be conveniently presented in dosageunit form and can be prepared by any of the methods well known in theart of pharmacy. The pharmaceutical compositions can be, for example,prepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier, a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredtherapeutic effect.

The 2,4-pyrimidinediamine compounds can be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray nasal, vaginal, rectal, sublingual,urethral (e.g., urethral suppository) or topical routes ofadministration (e.g., gel, ointment, cream, aerosol, etc.) and can beformulated, alone or together, in suitable dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants, excipients, and vehicles appropriate for each route ofadministration. In addition to the treatment of warm-blooded animalssuch as mice, rats, horses, cattle, sheep, dogs, cats, and monkeys, thecompounds described herein can be effective in humans.

Administration of the compounds described herein, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages.

For topical administration, the JAK-selective compound(s) or prodrug(s)can be formulated as solutions, gels, ointments, creams, suspensions,etc., as are well-known in the art. Such formulations can be included ina patch or other transdermal delivery system or formulation, e.g., aformulation with ingredients specifically designed to aid transport ofthe compound through the skin and into the body tissues.

Systemic formulations include those designed for administration byinjection (e.g., subcutaneous, intravenous, intramuscular, intrathecal,or intraperitoneal injection) as well as those designed for transdermal,transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions,or emulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions can also contain formulating agents, such as suspending,stabilizing, and/or dispersing agents. The formulations for injectioncan be presented in unit dosage form, e.g., in ampules or in multidosecontainers, and can contain added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, and dextrose solution, before use.To this end, the active compound(s) can be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions can take theform of, for example, lozenges, tablets, or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone,or hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose, or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars, films, or enteric coatings. Additionally,the pharmaceutical compositions containing the 2,4-substitutedpyrmidinediamine as active ingredient or prodrug thereof in a formsuitable for oral use can also include, for example, troches, lozenges,aqueous, or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use can be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions can contain one or more agents including sweetening agents,flavoring agents, coloring agents, and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient (including drug and/or prodrug) inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients can be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents (e.g., corn starch or alginic acid); bindingagents (e.g. starch, gelatin, or acacia); and lubricating agents (e.g.,magnesium stearate, stearic acid, or talc). The tablets can be leftuncoated or they can be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. They can also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. The pharmaceutical compositionsdescribed herein can also be in the form of oil-in-water emulsions.

Liquid preparations for oral administration can take the form of, forexample, elixirs, solutions, syrups, or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives, orhydrogenated edible fats); emulsifying agents (e.g., lecithin, oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™, or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations can also contain buffer salts, preservatives, flavoring,coloring, and sweetening agents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound, as is well known.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in the conventional manner.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or othersuitable gas). In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for example,capsules and cartridges including gelatin) can be formulated containinga powder mix of the compound and a suitable powder base such as lactoseor starch.

The pharmaceutical compositions can be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension can beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation can also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent. Among the acceptable vehicles and solvents that can be employedare water, Ringer's solution, and isotonic sodium chloride solution. The2,4-pyrimidinediamine compounds can also be administered in the form ofsuppositories for rectal or urethral administration of the drug. Forrectal and vaginal routes of administration, the active compound(s) canbe formulated as solutions (for retention enemas), suppositories, orointments containing conventional suppository bases such as cocoa butteror other glycerides. In particular embodiments, the compounds can beformulated as urethral suppositories, for example, for use in thetreatment of fertility conditions, particularly in males (e.g., for thetreatment of testicular dysfunction).

The disclosed 2,4-pyrimidinediamine compounds can be used formanufacturing a composition or medicament, including medicamentssuitable for rectal or urethral administration. Also specificallycontemplated herein are methods for manufacturing compositions includingthe presently disclosed 2,4-pyrimidinediamine compounds in a form thatis suitable for urethral or rectal administration, includingsuppositories.

For topical use, creams, ointments, jellies, gels, solutions,suspensions, etc., containing the 2,4-pyrimidinediamine compounds can beemployed. In certain embodiments, the 2,4-pyrimidinediamine compoundscan be formulated for topical administration with polyethylene glycol(PEG). These formulations can optionally include additionalpharmaceutically acceptable ingredients such as diluents, stabilizers,and/or adjuvants. In particular embodiments, the topical formulationsare formulated for the treatment of allergic conditions and/or skinconditions including psoriasis, contact dermatitis, and atopicdermatitis, among others described herein.

The presently disclosed 2,4-pyrimidinediamine compounds can be used formanufacturing a composition or medicament, including medicamentssuitable for topical administration. Accordingly, specificallycontemplated are methods for manufacturing compositions including2,4-pyrimidinediamine compounds in a form that is suitable for topicaladministration.

The presently disclosed 2,4-pyrimidinediamine compounds can also bedelivered by any of a variety of inhalation devices and methods known inthe art, including, for example: U.S. Pat. No. 6,241,969; U.S. Pat. No.6,060,069; U.S. Pat. No. 6,238,647; U.S. Pat. No. 6,335,316; U.S. Pat.No. 5,364,838; U.S. Pat. No. 5,672,581; WO96/32149; WO95/24183; U.S.Pat. No. 5,654,007; U.S. Pat. No. 5,404,871; U.S. Pat. No. 5,672,581;U.S. Pat. No. 5,743,250; U.S. Pat. No. 5,419,315; U.S. Pat. No.5,558,085; WO98/33480; U.S. Pat. No. 5,364,833; U.S. Pat. No. 5,320,094;U.S. Pat. No. 5,780,014; U.S. Pat. Nos. 5,658,878; 5,518,998; 5,506,203;U.S. Pat. No. 5,661,130; U.S. Pat. No. 5,655,523; U.S. Pat. No.5,645,051; U.S. Pat. No. 5,622,166; U.S. Pat. No. 5,577,497; U.S. Pat.No. 5,492,112; U.S. Pat. No. 5,327,883; U.S. Pat. No. 5,277,195; U.S.Pat. App. No. 20010041190; U.S. Pat. App. No. 20020006901; and U.S. Pat.App. No. 20020034477.

Included among the devices which can be used to administer particularexamples of the 2,4-pyrimidinediamine compounds are those well-known inthe art, such as metered dose inhalers, liquid nebulizers, dry powderinhalers, sprayers, thermal vaporizers, and the like. Other suitabletechnology for administration of particular 2,4-pyrimidinediaminecompounds includes electrohydrodynamic aerosolizers.

In addition, the inhalation device is preferably practical, in the senseof being easy to use, small enough to carry conveniently, capable ofproviding multiple doses, and durable. Some specific examples ofcommercially available inhalation devices are Turbohaler (Astra,Wilmington, Del.), Rotahaler (Glaxo, Research Triangle Park, N.C.),Diskus (Glaxo, Research Triangle Park, N.C.), the Ultravent nebulizer(Mallinckrodt), the Acorn II nebulizer (Marquest Medical Products,Totowa, N.J.) the Ventolin metered dose inhaler (Glaxo, ResearchTriangle Park, N.C.), and the like. In one embodiment,2,4-pyrimidinediamine compounds can be delivered by a dry powder inhaleror a sprayer.

As those skilled in the art will recognize, the formulation of2,4-pyrimidinediamine compounds, the quantity of the formulationdelivered, and the duration of administration of a single dose depend onthe type of inhalation device employed as well as other factors. Forsome aerosol delivery systems, such as nebulizers, the frequency ofadministration and length of time for which the system is activated willdepend mainly on the concentration of 2,4-pyrimidinediamine compounds inthe aerosol. For example, shorter periods of administration can be usedat higher concentrations of 2,4-pyrimidinediamine compounds in thenebulizer solution. Devices such as metered dose inhalers can producehigher aerosol concentrations and can be operated for shorter periods todeliver the desired amount of 2,4-pyrimidinediamine compounds in someembodiments. Devices such as dry powder inhalers deliver active agentuntil a given charge of agent is expelled from the device. In this typeof inhaler, the amount of 2,4-pyrimidinediamine compounds in a givenquantity of the powder determines the dose delivered in a singleadministration. The formulation of 2,4-pyrimidinediamine is selected toyield the desired particle size in the chosen inhalation device.

Formulations of 2,4-pyrimidinediamine compounds for administration froma dry powder inhaler may typically include a finely divided dry powdercontaining 2,4-pyrimidinediamine compounds, but the powder can alsoinclude a bulking agent, buffer, carrier, excipient, another additive,or the like. Additives can be included in a dry powder formulation of2,4-pyrimidinediamine compounds, for example, to dilute the powder asrequired for delivery from the particular powder inhaler, to facilitateprocessing of the formulation, to provide advantageous powder propertiesto the formulation, to facilitate dispersion of the powder from theinhalation device, to stabilize to the formulation (e.g., antioxidantsor buffers), to provide taste to the formulation, or the like. Typicaladditives include mono-, di-, and polysaccharides; sugar alcohols andother polyols, such as, for example, lactose, glucose, raffinose,melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, or lecithin; and the like.

Examples of the presently disclosed 2,4-pyrimidinediamine compounds alsoare suitable for administration by inhalation. For example, thepresently disclosed 2,4-pyrimidinediamine compounds can be used formanufacturing a composition or medicament, including medicamentssuitable for administration by inhalation. Accordingly, the presentdisclosure includes methods for manufacturing compositions including thepresently disclosed 2,4-pyrimidinediamine compounds in a form that issuitable for administration, including administration by inhalation. Forexample, a dry powder formulation can be manufactured in several ways,using conventional techniques, such as described in any of thepublications mentioned above and incorporated expressly herein byreference, and, for example, Baker, et al., U.S. Pat. No. 5,700,904, theentire disclosure of which is incorporated expressly herein byreference. Particles in the size range appropriate for maximaldeposition in the lower respiratory tract can be made by micronizing,milling, or the like. A liquid formulation can be manufactured bydissolving one or more of the presently 2,4-pyrimidinediamine compoundsin a suitable solvent, such as water, at an appropriate pH, includingbuffers or other excipients.

For ocular administration, the 2,4-pyrimidinediamine compound(s) orprodrug(s) can be formulated as a solution, emulsion, suspension, etc.,suitable for administration to the eye. Administration to the eye isgenerally via topical exposure of the eye to the formulation, but alsoincludes injection into the eye if necessary. A variety of vehiclessuitable for administering compounds to the eye are known in the art.Specific non-limiting examples are described in U.S. Pat. No. 6,261,547;U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No.5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat.No. 5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S.Pat. No. 4,882,150; and U.S. Pat. No. 4,738,851.

Typically formulations for ocular administration contain apharmaceutically effective amount of a 2,4-pyrimidinediamine compounddisclosed herein, such as from about 0.0001% to about 1.0% by weight(w/w). In certain formulations, the pharmaceutically effective amount ofthe compound is 0.0003% to about 0.1% (w/w), such as from about 0.003%to about 0.5% (w/w), or from about 0.01% to about 0.03% (w/w).

In certain examples an ophthalmic composition containing a presentlydisclosed 2,4-pyrimidinediamine compound for ocular administrationincludes a tonicity agent, a buffer, or both. In certain examples ofophthalmic compositions the tonicity agent is a simple carbohydrate or asugar alcohol. As is known to those of skill in the art, tonicity agentsmay be used in the present compositions to adjust the tonicity of thecomposition, preferably to that of normal tears. Examples of suitabletonicity agents include, without limitation sodium chloride, potassiumchloride, magnesium chloride, calcium chloride, carbohydrates, such asdextrose, fructose, galactose, polyols, such as sugar alcohols,including by way of example, mannitol, sorbitol, xylitol, lactitol,isomalt, maltitol and combinations thereof. Compositions containing abuffer contain, in some examples, a phosphate, citrate, or both.

In one aspect, compositions for ocular administration of the presentlydisclosed 2,4-pyrimidinediamine compounds optionally contain asurfactant, a stabilizing polymer, or both. Surfactants are employed incertain compositions to facilitate the delivery of higher concentrationsof the 2,4-pyrimidinediamine compound being administered. Suchsurfactants can work to solubilize the compound. Exemplary surfactantsinclude polysorbate, poloxamer, polyoxyl 40 stearate, polyoxyl castoroil, tyloxapol, triton and sorbitan monolaurate. In certain embodimentsthe surfactant is selected from Triton X114, tyloxapol and combinationsthereof. In still another embodiment of compositions for ocularadministration, the stabilizing polymer is carbomer 974p.

For prolonged delivery, the 2,4-pyrimidinediamine compound(s) orprodrug(s) can be formulated as a depot preparation for administrationby implantation or intramuscular injection. The active ingredient can beformulated with suitable polymeric or hydrophobic materials (e.g., as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives (e.g., as a sparingly soluble salt). Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in, for example, U.S. Pat. No. 5,407,713; U.S.Pat. No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168;U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No.5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat.No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) can also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions can, if desired, be presented in a packor dispenser device which can contain one or more unit dosage formscontaining the active compound(s). The pack can, for example, includemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

Another embodiment is a kit including a compound, prodrug orpharmaceutical composition as described in any of the embodiments above.Kit embodiments are described in more detail below.

Methods

The present invention provides 2,4-pyrimidinediamine compounds, prodrugsand pharmaceutical compositions thereof, as described herein, for use intherapy for the conditions described herein. The present inventionfurther provides use of the compounds of the present invention in themanufacture of a medicament for the treatment of conditions in whichtargeting of the JAK pathway or inhibition of JAK kinases, particularlyJAK3, are therapeutically useful. These include conditions where thefunction of lymphocytes, macrophages, or mast cells is involved.Conditions in which targeting of the JAK pathway or inhibition of theJAK kinases, particularly JAK3, are therapeutically useful includeleukemia, lymphoma, transplant rejection (e.g., pancreas islettransplant rejection), bone marrow transplant applications (e.g.,graft-versus-host disease), autoimmune diseases (e.g., rheumatoidarthritis, etc.), inflammation (e.g., asthma, etc.) and other conditionsas described in greater detail herein.

In another embodiment, the methods can be practiced as a therapeuticapproach towards the treatment of the conditions described herein. Thus,in a specific embodiment, the 2,4-pyrimidinediamine compounds (and thevarious forms described herein, including pharmaceutical formulationsincluding the compounds (in the various forms)) can be used to treat theconditions described herein in animal subjects, including humans. Themethods generally include administering to the subject an amount of acompound described herein, or a salt, prodrug, hydrate, or N-oxidethereof, effective to treat the condition. In one embodiment, thesubject is a non-human mammal, including, but not limited to, bovine,horse, feline, canine, rodent, or primate. In another embodiment, thesubject is a human.

As noted previously, numerous conditions can be treated using the2,4-substituted pyrimidinediamine compounds, prodrugs thereof, andmethods of treatment as described herein. As used herein, “Treating” or“treatment” of a disease in a patient refers to (1) preventing thedisease from occurring in a patient that is predisposed or does not yetdisplay symptoms of the disease; (2) inhibiting the disease or arrestingits development; or (3) ameliorating or causing regression of thedisease. As well understood in the art, “treatment” is an approach forobtaining beneficial or desired results, including clinical results. Forthe purposes of this invention, beneficial or desired results caninclude one or more, but are not limited to, alleviation or ameliorationof one or more symptoms, diminishment of extent of a condition,including a disease, stabilized (i.e., not worsening) state of acondition, including diseases, preventing spread of disease, delay orslowing of condition, including disease, progression, amelioration orpalliation of the condition, including disease, state, and remission(whether partial or total), whether detectable or undetectable.Preferred are compounds that are relatively potent compared to the classas a whole and can be administered at low doses, preferably but notnecessarily locally, thus minimizing systemic adverse effects.

The compounds described herein are potent and selective inhibitors ofJAK kinases and are particularly selective for cytokine signalingpathways containing JAK3. As a consequence of this activity, thecompounds can be used in a variety of in vitro, in vivo, and ex vivocontexts to regulate or inhibit JAK kinase activity, signaling cascadesin which JAK kinases play a role, and the biological responses effectedby such signaling cascades. For example, in one embodiment, thecompounds can be used to inhibit JAK kinase, either in vitro or in vivo,in virtually any cell type expressing the JAK kinase, such as inhematopoietic cells in which, for example, JAK3 is predominantlyexpressed. They can also be used to regulate signal transductioncascades in which JAK kinases, particularly JAK3, play a role. SuchJAK-dependent signal transduction cascades include, but are not limitedto, the signaling cascades of cytokine receptors that involve the commongamma chain, such as, for example, the IL-4, IL-7, IL-5, IL-9, IL-15 andIL-21, or IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor signalingcascades. The compounds can also be used in vitro or in vivo toregulate, and in particular to inhibit, cellular or biological responsesaffected by such JAK-dependent signal transduction cascades. Suchcellular or biological responses include, but are not limited to,IL-4/ramos CD23 upregulation and IL-2 mediated T-cell proliferation.Importantly, the compounds can be used to inhibit JAK kinases in vivo asa therapeutic approach towards the treatment or prevention of diseasesmediated, either wholly or in part, by a JAK kinase activity (referredto herein as “JAK kinase mediated diseases”). Non-limiting examples ofJAK kinase mediated diseases that can be treated or prevented with thepresently disclosed compounds include, but are not limited to, thefollowing: allergies; asthma; autoimmune diseases, including systemicautoimmune disorders, transplant rejection (e.g., kidney, heart, lung,liver, pancreas, skin; host versus graft reaction (HVGR), and graftversus host reaction (GVHR)), rheumatoid arthritis, and amyotrophiclateral sclerosis; T-cell mediated autoimmune diseases such as multiplesclerosis, psoriasis, and Sjogren's syndrome; Type II inflammatorydiseases such as vascular inflammation (including vasculitis, arteritis,atherosclerosis, and coronary artery disease); diseases of the centralnervous system such as stroke; pulmonary diseases such as bronchitisobliteraus and primary pulmonary hypertension; solid, delayed Type IVhypersensitivity reactions; and hematologic malignancies such asleukemia and lymphomas.

One embodiment is a method as described below employed with a compoundaccording to formula I, or in a more specific embodiment, a compoundaccording to formula IA, IA1, IA2, IA3, IB, IB1, IB2, IB3 and/or II, orin an even more specific embodiment, a species described herein. Forbrevity, the methods described below reference a compound of formula I,but corresponding methods according to the various compound andcomposition subgenus and species are also meant to be included.

One embodiment is a method of inhibiting an activity of a JAK kinase,including contacting the JAK kinase with an amount of a compound,effective to inhibit an activity of the JAK kinase, of formula I:

or salt thereof, wherein:

-   -   X and Y are each independently O, S, S(O), SO₂ or NR¹;    -   each R¹ is independently for each occurrence H, optionally        substituted C₁₋₆alkyl, C(O)—C₁₋₆alkyl, CO₂—C₁₋₆alkyl or R⁵⁰;    -   each R⁵⁰ is —C(R⁹)₂-A-R¹⁰, where A is O or S; each R⁹ is        independently for each occurrence H, optionally substituted        C₁₋₆alkyl, optionally substituted C₆₋₁₀aryl or optionally        substituted C₇₋₁₆arylalkyl; or alternatively, two R⁹, together        with the carbon to which they are attached, form an optionally        substituted C₃₋₈cycloalkyl group or an optionally substituted        3-8 membered heteroalicyclyl; R¹⁰ is R^(a) or —P(O)(OR¹¹)₂; each        R¹¹ is independently for each occurrence R^(a) or a monovalent        cationic group; or two R¹¹, together with the atoms to which        they are attached, form a 4-8 membered cyclic phosphate group,        or two R¹¹ together represent a divalent cationic group;    -   ring A is a C₆₋₁₀aryl or a 5-10 membered heteroaryl;    -   each R² is independently for each occurrence H, R^(e), R^(b),        R^(e) substituted with one or more of the same or different        R^(a) and/or R^(b), —OR^(e) substituted with one or more of the        same or different R^(a) and/or R^(b), —SR^(e) substituted with        one or more of the same or different R^(a) and/or R^(b),        —C(O)R^(e) substituted with one or more of the same or different        R^(a) and/or R^(b), —N(R^(a))R^(e) where R^(e) is substituted        with one or more of the same or different R^(a) and/or R^(b),        —S(O)₂R^(e) substituted with one or more of the same or        different R^(a) and/or R^(b), —N(R^(a))—S(O)₂R^(e) where R^(e)        is substituted with one or more of the same or different R^(a)        and/or R^(b), —B(OR^(a))₂, —B(N(R^(c))₂)₂,        —(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(a))₂)_(m)—R^(b),        —S(C(R^(a))₂)_(m)R^(b), —O—(C(R^(b))₂)_(m)—R^(a),        —N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),        —C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —O—(C(R^(a))₂)_(m)C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N((C(R^(a))₂)_(m)R^(b))₂,        —S—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N(R^(a))—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b),        —N(R^(a))—C(O)—(C(R^(a))₂)_(m)—C(R^(a))(R^(b))₂ or        —N(R^(a))—(C(R^(a))₂)_(m)—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b);    -   each R^(a) is independently for each occurrence H, deuterium,        C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,        C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-10 membered        heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15        membered heteroaryl or 6-16 membered heteroarylalkyl;    -   each R^(b) is independently for each occurrence ═O, —OR^(a),        —O—(C(R^(a))₂)_(m)—OR^(a), haloC₁₋₃alkyloxy, ═S, —SR^(a),        ═NR^(a), ═NOR^(a), —N(R^(c))₂, halo, —CF₃, —CN, —NC, —OCN, —SCN,        —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O)₂R^(a), —SO₃R^(a),        —S(O)N(R^(c))₂, —S(O)₂N(R^(c))₂, —OS(O)R^(a), —OS(O)₂R^(a),        —OSO₃R^(a), —OS(O)₂N(R^(c))₂, —C(O)R^(a), —CO₂R^(a),        —C(O)N(R^(c))₂, —C(NR^(a))—N(R^(c))₂, —C(NOH)—R^(a),        —C(NOH)—N(R^(c))₂, —OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(c))₂,        —OC(NH)—N(R^(c))₂, —OC(NR^(a))—N(R^(c))₂, —N(R^(a))—S(O)₂H,        —[N(R^(a))C(O)]R^(a), —[N(R^(a))C(O)]OR^(a),        —[N(R^(a))C(O)]_(n)N(R^(c))₂ or        —[N(R^(a))C(NR^(a))]_(n)—N(R^(c))₂;    -   each R^(c) is independently for each occurrence R^(a), or,        alternatively, two R^(c) are taken together with the nitrogen        atom to which they are bonded to form a 3 to 10-membered        heteroalicyclyl or a 5-10 membered heteroaryl which may        optionally include one or more of the same or different        additional heteroatoms and which is optionally substituted with        one or more of the same or different R^(a) and/or R^(d) groups;    -   each R^(d) is ═O, —OR^(a), haloC₁₋₃alkyloxy, C₁₋₆alkyl, ═S,        —SR^(a), ═NR^(a), ═NOR^(a), —N(R^(a))₂, halo, —CF₃, —CN, —NC,        —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O₂)R^(a),        —SO₃R^(a), —S(O)N(R^(a))₂, —S(O)₂N(R^(a))₂, —OS(O)R^(a),        —OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(a))₂, —C(O)R^(a),        —CO₂R^(a), —C(O)N(R^(a))₂, —C(NR^(a))N(R^(a))₂, —C(NOH)R^(a),        —C(NOH)N(R^(a))₂, —OCO₂R^(a), —OC(O)N(R^(a))₂,        —OC(NR^(a))N(R^(a))₂, —[N(R^(a))C(O)]_(n)R^(a),        (C(R^(a))₂)_(n)—OR^(a), —N(R^(a))—S(O)₂R^(a),        —C(O)—C₁₋₆haloalkyl, —S(O)₂C₁₋₆haloalkyl, —OC(O)R^(a),        —O(C(R^(a))₂)_(m)—OR^(a), —S(C(R^(a))₂)_(m)—OR^(a),        —N(R^(a))C₁₋₆haloalkyl, —P(O)(OR^(a))₂,        —N(R^(a))—(C(R^(a))₂)_(m)—OR^(a), —[N(R^(a))C(O)]_(n)OR^(a),        —[N(R^(a))C(O)]_(n)N(R^(a))₂, —[N(R^(a))C(NR^(a))]_(n)N(R^(a))₂        or —N(R^(a))C(O)C₁₋₆haloalkyl; two R^(d), taken together with        the atom or atoms to which they are attached, combine to form a        3-10 membered partially or fully saturated mono or bicyclic        ring, optionally containing one or more heteroatoms and        optionally substituted with one or more R^(a);    -   each R^(e) is independently for each occurrence C₁₋₆alkyl,        C₃₋₈cycloalkyl, C₄₋₁₁ cycloalkylalkyl, C₆₋₁₀aryl,        C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-10 membered        heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15        membered heteroaryl or 6-16 membered heteroarylalkyl;    -   p is 0, 1, 2, 3 or 4;    -   each m is 1, 2 or 3;    -   each n is 0, 1, 2 or 3;    -   two R² groups, taken together with the atom or atoms to which        they are attached, combine to form a 4-10 membered partially or        fully saturated mono or bicyclic ring, optionally containing one        or more heteroatoms and optionally substituted with one or more        R^(a) and/or R^(b);    -   Z¹ and Z² are each independently CH, CR² or N;    -   R³ is H, optionally substituted C₁₋₆alkyl or R⁵⁰;    -   R⁴ is H, optionally substituted C₁₋₆alkyl or R⁵⁰; and    -   R⁵ is halo, —CN, optionally substituted C₁₋₆alkyl, alkynyl,        hydroxy, optionally substituted C₁₋₆alkoxy, nitro, —N(R^(a))₂,        —C(O)N(R^(a))₂, —CO₂R^(a) or —C(O)R^(a).

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, including contacting the JAK kinase with anamount of a compound effective to inhibit an activity of the JAK kinase,where the compound is according to formula I, as described herein. Incertain embodiments of the methods described herein, the method iscarried out in vivo.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, including contacting in vitro a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase, where the compound is according to formula I, as describedherein.

In a specific embodiment, the compounds can be used to treat and/orprevent rejection in organ and/or tissue transplant recipients (i.e.,treat and/or prevent allograft rejection). Allografts can be rejectedthrough either a cell-mediated or humoral immune reaction of therecipient against transplant (histocompability) antigens present on themembranes of the donor's cells. The strongest antigens are governed by acomplex of genetic loci termed human leukocyte group A (HLA) antigens.Together with the ABO blood groups antigens, they are the chieftransplantation antigens detectable in humans.

Rejection following transplantation can generally be broken into threecategories:

hyperacute, occurring hours to days following transplantation; acute,occurring days to months following transplantation; and chronic,occurring months to years following transplantation.

Hyperacute rejection is caused mainly by the production of hostantibodies that attack the graft tissue. In a hyperacute rejectionreaction, antibodies are observed in the transplant vascular very soonafter transplantation. Shortly thereafter, vascular clotting occurs,leading to ischemia, eventual necrosis and death. The graft infarctionis unresponsive to known immunosuppressive therapies. Because HLAantigens can be identified in vitro, pre-transplant screening is used tosignificantly reduce hyperacute rejection. As a consequence of thisscreening, hyperacute rejection is relatively uncommon today.

Acute rejection is thought to be mediated by the accumulation of antigenspecific cells in the graft tissue. The T-cell-mediated immune reactionagainst these antigens (i.e., HVGR or GVHR) is the principle mechanismof acute rejection. Accumulation of these cells leads to damage of thegraft tissue. It is believed that both CD4+ helper T-cells and CD8+cytotoxic T-cells are involved in the process and that the antigen ispresented by donor and host dendritic cells. The CD4+ helper T-cellshelp recruit other effector cells, such as macrophapges and eosinophils,to the graft. Accessing T-cell activation signal transduction cascades(for example, CD28, CD40L, and CD2 cascades) are also involved.

The cell-mediated acute rejection can be reversed in many cases byintensifying immunotherapy. After successful reversal, severely damagedelements of the graft heal by fibrosis and the remainder of the graftappears normal. After resolution of acute rejection, dosages ofimmunosuppressive drugs can be reduced to very low levels.

Chronic rejection, which is a particular problem in renal transplants,often progresses insidiously despite increased immunosuppressivetherapy. It is thought to be due, in large part, to cell-mediated TypeIV hypersensitivity. The pathologic profile differs from that of acuterejection. The arterial endothelium is primarily involved with extensiveproliferation that may gradually occlude the vessel lumen, leading toischemia, fibrosis, a thickened intima, and atherosclerotic changes.Chronic rejection is mainly due to a progressive obliteration of graftvasculature and resembles a slow, vasculitic process.

In Type IV hypersensitivity, CD8 cytotoxic T-cells and CD4 helper Tcells recognize either intracellular or extracellular synthesizedantigen when it is complexed, respectively, with either Class I or ClassII MHC molecules. Macrophages function as antigen-presenting cells andrelease IL-1, which promotes proliferation of helper T-cells. HelperT-cells release interferon gamma and IL-2, which together regulatedelayed hyperactivity reactions mediated by macrophage activation andimmunity mediated by T cells. In the case of organ transplant, thecytotoxic T-cells destroy the graft cells on contact.

Since JAK kinases play a critical role in the activation of T-cells, the2,4-pyrimidinediamine compounds described herein can be used to treatand/or prevent many aspects of transplant rejection, and areparticularly useful in the treatment and/or prevention of rejectionreactions that are mediated, at least in part, by T-cells, such as HVGRor GVHR. The 2,4-pyrimidinediamine compounds can also be used to treatand/or prevent chronic rejection in transplant recipients and, inparticular, in renal transplant recipients. The compound can also beadministered to a tissue or an organ prior to transplanting the tissueor organ in the transplant recipient.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, including administering to a patientsuffering from such an autoimmune disease an amount of a compoundeffective to treat the autoimmune disease where the compound isaccording to formula I, as described herein. In certain embodiments ofthe methods the autoimmune disease is multiple sclerosis (MS),psoriasis, or Sjogran's syndrome.

Therapy using the 2,4-pyrimidinediamine compounds described herein canbe applied alone, or it can be applied in combination with or adjunctiveto other common immunosuppressive therapies, such as, for example, thefollowing: mercaptopurine; corticosteroids such as prednisone;methylprednisolone and prednisolone; alkylating agents such ascyclophosphamide; calcineurin inhibitors such as cyclosporine,sirolimus, and tacrolimus; inhibitors of inosine monophosphatedehydrogenase (IMPDH) such as mycophenolate, mycophenolate mofetil, andazathioprine; and agents designed to suppress cellular immunity whileleaving the recipient's humoral immunologic response intact, includingvarious antibodies (for example, antilymphocyte globulin (ALG),antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3))and irradiation. These various agents can be used in accordance withtheir standard or common dosages, as specified in the prescribinginformation accompanying commercially available forms of the drugs (seealso: the prescribing information in the 2006 Edition of The Physician'sDesk Reference), the disclosures of which are incorporated herein byreference. Azathioprine is currently available from SalixPharmaceuticals, Inc., under the brand name AZASAN; mercaptopurine iscurrently available from Gate Pharmaceuticals, Inc., under the brandname PURINETHOL; prednisone and prednisolone are currently availablefrom Roxane Laboratories, Inc.; Methyl prednisolone is currentlyavailable from Pfizer; sirolimus (rapamycin) is currently available fromWyeth-Ayerst under the brand name RAPAMUNE; tacrolimus is currentlyavailable from Fujisawa under the brand name PROGRAF; cyclosporine iscurrent available from Novartis under the brand name SANDIMMUNE and fromAbbott under the brand name GENGRAF; IMPDH inhibitors such asmycophenolate mofetil and mycophenolic acid are currently available fromRoche under the brand name CELLCEPT and from Novartis under the brandname MYFORTIC; azathioprine is currently available from Glaxo SmithKline under the brand name IMURAN; and antibodies are currentlyavailable from Ortho Biotech under the brand name ORTHOCLONE, fromNovartis under the brand name SIMULECT (basiliximab), and from Rocheunder the brand name ZENAPAX (daclizumab).

In another embodiment, the 2,4-pyrimidinediamine compounds could beadministered either in combination or adjunctively with an inhibitor ofa Syk kinase. Syk kinase is a tyrosine kinase known to play a criticalrole in Fcγ receptor signaling, as well as in other signaling cascades,such as those involving B-Cell receptor signaling (Tumer et al., (2000),Immunology Today 21:148-154) and integrins beta (1), beta (2), and beta(3) in neutrophils (Mocsavi et al., (2002), Immunity 16:547-558). Forexample, Syk kinase plays a pivotal role in high affinity IgE receptorsignaling in mast cells that leads to activation and subsequent releaseof multiple chemical mediators that trigger allergic attacks. However,unlike the JAK kinases, which help regulate the pathways involved indelayed or cell-mediated Type IV hypersensitivity reactions, Syk kinasehelps regulate the pathways involved in immediate IgE-mediated, Type Ihypersensitivity reactions. Certain compounds that affect the Sykpathway may or may not also affect the JAK pathways.

Suitable Syk inhibitory compounds are described, for example, in Ser.No. 10/355,543 filed Jan. 31, 2003 (publication no. 2004/0029902); WO03/063794; Ser. No. 10/631,029 filed Jul. 29, 2003 (publication no.2007/0060603); WO 2004/014382; Ser. No. 10/903,263 filed Jul. 30, 2004(publication no. 2005/0234049); PCT/US2004/24716 filed Jul. 30, 2004(WO005/016893); Ser. No. 10/903,870 filed Jul. 30, 2004 (publication no.2005/0209224); PCT/US2004/24920 filed Jul. 30, 2004; Ser. No. 60/630,808filed Nov. 24, 2004; Ser. No. 60/645,424 filed Jan. 19, 2005; and Ser.No. 60/654,620, filed Feb. 18, 2005, the disclosures of which areincorporated herein by reference. The 2,4-pyrimidinediamine describedherein and Syk inhibitory compounds could be used alone or incombination with one or more conventional transplant rejectiontreatments, as described above.

In a specific embodiment, the 2,4-pyrimidinediamine compounds can beused to treat or prevent these diseases in patients that are eitherinitially non-responsive (resistant) to or that become non-responsive totreatment with a Syk inhibitory compound or one of the other currenttreatments for the particular disease. The 2,4-pyrimidinediaminecompounds could also be used in combination with Syk inhibitorycompounds in patients that are Syk-compound resistant or non-responsive.Suitable Syk-inhibitory compounds with which the 2,4-pyrimidinediaminecompounds can be administered are provided supra.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, including administering to a patientsuffering from such an autoimmune disease an amount of a compoundaccording to formula I, in combination with or adjunctively to acompound that inhibits Syk kinase with an IC₅₀ of at least 10 μM,effective to treat the autoimmune disease.

In another embodiment, this invention provides a method of treatingallograft transplant rejection, either acute or chronic, in a transplantrecipient, including administering to the transplant recipient an amountof a compound according to formula I effective to treat or prevent therejection. In a further embodiment, the compound is administered to atissue or an organ prior to or concurrent with, transplanting the tissueor organ in the transplant recipient. In another embodiment, thecompound is administered to the tissue or organ and the patient. In aspecific embodiment the allograft transplant rejection is mediated byHVGR or GVHR. In another embodiment, the allograft transplant organ is akidney, a heart, a liver, or a lung. In another embodiment, in which theallograft transplant organ is a kidney, a heart, a liver, or a lung, thecompound is administered in combination with or adjunctively to anotherimmunosuppressant. In a more specific embodiment, the immunosuppressantis cyclosporine, tacrolimus, sirolimus, an inhibitor of IMPDH,mycophenolate, mycophanolate mofetil, an anti-T-Cell antibody or OKT3.

The 2,4-pyrimidinediamine compounds described herein are cytokinemoderators of IL-4 signaling. As a consequence, the2,4-pyrimidinediamine compounds could slow the response of Type Ihypersensitivity reactions. Thus, in a specific embodiment, the2,4-pyrimidinediamine compounds could be used to treat such reactionsand, therefore, the diseases associated with, mediated by, or caused bysuch hypersensitivity reactions (for example, allergies),prophylactically. For example, an allergy sufferer could take one ormore of the JAK selective compounds described herein prior to expectedexposure to allergens to delay the onset or progress of, or eliminatealtogether, an allergic response.

When used to treat or prevent such diseases, the 2,4-pyrimidinediaminecompounds can be administered singly, as mixtures of one or more2,4-pyrimidinediamine compounds, or in mixture or combination with otheragents useful for treating such diseases and/or the symptoms associatedwith such diseases. The 2,4-pyrimidinediamine compounds can also beadministered in mixture or in combination with agents useful to treatother disorders or maladies, such as steroids, membrane stabilizers,5-lipoxygenase (5L0) inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs,rituximab, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, andantihistamines, to name a few. The 2,4-pyrimidinediamine compounds canbe administered per se in the form of prodrugs or as pharmaceuticalcompositions, including an active compound.

In another embodiment, this invention provides a method of treating aType IV hypersensitivity reaction, including administering to a subjectan amount of a compound effective to treat or prevent thehypersensitivity reaction, where the compound is according to formula I,as described herein. In one embodiment, the method is practicedprophylactically. In some embodiments, the compound is administeredprior to exposure to an allergen.

In another embodiment, this invention provides a method of inhibiting asignal transduction cascade in which JAK3 kinase plays a role, includingcontacting a cell expressing a receptor involved in such a signalingcascade with a compound, where the compound is according to formula I,as described herein.

In another embodiment, this invention provides a method of treating aJAK kinase-mediated disease, including administering to a subject anamount of compound effective to treat or prevent the JAK kinase-mediateddisease, where the compound is according to formula I, as describedherein.

In another embodiment, this invention provides a method of treating aJAK kinase-mediated disease, in which the JAK-mediated disease is HVGRor GVHR, including administering to a subject an amount of compoundeffective to treat or prevent the JAK kinase-mediated disease, where thecompound is according to formula I, as described herein.

In another embodiment, ocular disorders are treated using an effectiveamount of a compound of formula I, as described herein. In one aspect ofthe disclosed method for treating ocular disorders, administration ofone or more of the presently disclosed 2,4-pyrimidinediamine compoundsis effective to increase tear production volume as compared to untreatedtear production volume, thereby ameliorating a symptom of dry eyesyndrome. In one aspect, tear production volume is increased within fivedays, such as in less than four days, and in some examples in less thantwo days. In one embodiment, tear production volume is increased by atleast about 25% over initial tear production within two days of initialtreatment with a presently disclosed 2,4-pyrimidinediamine compound. Inother embodiments, tear production is increased at least about 30%, suchas at least about 50% over initial tear production within less than twodays. Increases in tear production upon administration of the presentcompounds results, in some instances, in tear production volumecomparable to normal tear production. Typically the disclosed compounds,when used for treating ocular disorders topically, are administered atleast once daily and typically at most twice a day.

As mentioned, another embodiment provides a method of treating a diseaseand/or disorder of the eye, which includes administering to a subject anamount of a compound effective to treat the disease and/or disorder ofthe eye wherein the compound is according to formula I, as describedherein. Diseases and disorders of the eye include, but are not limitedto, dry eye syndrome, uveitis, allergic conjunctivitus, glaucoma androsacea (of the eye). Dry eye syndrome (DES), otherwise known askeratoconjunctivitis sicca (KCS), keratitis sicca, sicca syndrome, orxerophthalmia, is an eye disease caused by decreased tear production orincreased tear film evaporation commonly found in humans and someanimals. Uveitis or iridocyclitis refers to inflammation of the middlelayer of the eye (the “uvea”) and in common usage may refer to anyinflammatory process involving the interior of the eye. Allergicconjunctivitis is inflammation of the conjunctiva (the membrane coveringthe white part of the eye) due to allergy. Glaucoma refers to a group ofdiseases that affect the optic nerve and involves a loss of retinalganglion cells in a characteristic pattern, i.e., a type of opticneuropathy. Raised intraocular pressure is a significant risk factor fordeveloping glaucoma (above 22 mmHg or 2.9 kPa), and inflammatoryprocesses, e.g. uveitis, can cause this rise in intraocular pressure.Rosacea is a chronic inflammatory condition characterized by facialerythema but it can affect the eyes. As mentioned, compounds describedherein may be used to treat inflammatory responses. While not wishing tobe bound by theory, it is believed that compounds described herein areeffective treatments of these eye disorders due, at least in part, totheir JAK inhibitory activity.

Active compounds described herein typically inhibit the JAK/Statpathway. The activity of a specified compound as an inhibitor of a JAKkinase can be assessed in vitro or in vivo. In some embodiments, theactivity of a specified compound can be tested in a cellular assay.Suitable assays include assays that determine inhibition of either thephosphorylation activity or ATPase activity of a JAK kinase. Thus, acompound is said to inhibit an activity of a JAK kinase if it inhibitsthe phosphorylation or ATPase activity of a JAK kinase with an IC₅₀ ofabout 20 μM or less.

“Cell proliferative disorder” refers to a disorder characterized byabnormal proliferation of cells. A proliferative disorder does not implyany limitation with respect to the rate of cell growth, but merelyindicates loss of normal controls that affect growth and cell division.Thus, in some embodiments, cells of a proliferative disorder can havethe same cell division rates as normal cells but do not respond tosignals that limit such growth. Within the ambit of “cell proliferativedisorder” is neoplasm or tumor, which is an abnormal growth of tissue.Cancer refers to any of various malignant neoplasms characterized by theproliferation of cells that have the capability to invade surroundingtissue and/or metastasize to new colonization sites.

“Hematopoietic neoplasm” refers to a cell proliferative disorder arisingfrom cells of the hematopoietic lineage. Generally, hematopoiesis is thephysiological process whereby undifferentiated cells or stem cellsdevelop into various cells found in the peripheral blood. In the initialphase of development, hematopoietic stem cells, typically found in thebone marrow, undergo a series of cell divisions to form multipotentprogenitor cells that commit to two main developmental pathways: thelymphoid lineage and the myeloid lineage. The committed progenitor cellsof the myeloid lineage differentiate into three major sub-branchesincluding the erythroid, megakaryocyte, and granulocyte/monocytedevelopmental pathways. An additional pathway leads to formation ofdendritic cells, which are involved in antigen presentation. Theerythroid lineage gives rise to red blood cells while the megakaryocyticlineage gives rise to blood platelets. Committed cells of thegranulocyte/monocyte lineage split into granulocyte or monocytedevelopmental pathways, the former pathway leading to formation ofneutrophils, eosinophils, and basophils and the latter pathway givingrise to blood monocytes and macrophages.

Committed progenitor cells of the lymphoid lineage develop into the Bcell pathway, T cell pathway, or the non-T/B cell pathway. Similar tothe myeloid lineage, an additional lymphoid pathway appears to give riseto dendritic cells involved in antigen presentation. The B cellprogenitor cell develops into a precursor B cell (pre-B), whichdifferentiates into B cells responsible for producing immunoglobulins.Progenitor cells of the T cell lineage differentiate into precursor Tcells (pre-T) that, based on the influence of certain cytokines, developinto cytotoxic or helper/suppressor T cells involved in cell mediatedimmunity. Non-T/B cell pathway leads to generation of natural killer(NK) cells. Neoplasms of hematopoietic cells can involve cells of anyphase of hematopoiesis, including hematopoietic stem cells, multipotentprogenitor cells, oligopotent committed progenitor cells, precursorcells, and mature differentiated cells. The categories of hematopoieticneoplasms can generally follow the descriptions and diagnostic criteriaemployed by those of skill in the art (see, e.g., InternationalClassification of Disease and Related Health Problems (ICD 10), WorldHealth Organization (2003)). Hematopoietic neoplasms can also becharacterized based on the molecular features, such as cell surfacemarkers and gene expression profiles, cell phenotype exhibited by theaberrant cells, and/or chromosomal aberrations (e.g., deletions,translocations, insertions, etc.) characteristic of certainhematopoietic neoplasms, such as the Philadelphia chromosome found inchronic myelogenous leukemia. Other classifications include NationalCancer Institute Working Formulation (Cancer, 1982, 49:2112-2135) andRevised European-American Lymphoma Classification (REAL).

“Lymphoid neoplasm” refers a proliferative disorder involving cells ofthe lymphoid lineage of hematopoiesis. Lymphoid neoplasms can arise fromhematopoietic stem cells as well as lymphoid committed progenitor cells,precursor cells, and terminally differentiated cells. These neoplasmscan be subdivided based on the phenotypic attributes of the aberrantcells or the differentiated state from which the abnormal cells arise.Subdivisions include, among others, B cell neoplasms, T cell neoplasms,NK cell neoplasms, and Hodgkin's lymphoma.

“Myeloid neoplasm” refers to proliferative disorder of cells of themyeloid lineage of hematopoiesis. Neoplasms can arise from hematopoieticstem cells, myeloid committed progenitor cells, precursor cells, andterminally differentiated cells. Myeloid neoplasms can be subdividedbased on the phenotypic attributes of the aberrant cells or thedifferentiated state from which the abnormal cells arise. Subdivisionsinclude, among others, myeloproliferative diseases,myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes,acute myeloid leukemia, and acute biphenotypic leukemia.

Generally cell proliferative disorders treatable with the compoundsdisclosed herein relate to any disorder characterized by aberrant cellproliferation. These include various tumors and cancers, benign ormalignant, metastatic or non-metastatic. Specific properties of cancers,such as tissue invasiveness or metastasis, can be targeted using themethods described herein. Cell proliferative disorders include a varietyof cancers, including, among others, breast cancer, ovarian cancer,renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer,pancreatic cancer, lung squamous carcinoma, and adenocarcinoma. Morespecifically, related to particular tissues, organs or areas of thebody, Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,lipo sarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinorna, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis defomians), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, SertoliLeydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma],fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal lands: neuroblastoma.The term “cancerous cell” as provided herein, includes a cell afflictedby any one of the above-identified conditions.

In some embodiments, the cell proliferative disorder treated is ahematopoietic neoplasm, which is aberrant growth of cells of thehematopoietic system. Hematopoietic malignancies can have its origins inpluripotent stem cells, multipotent progenitor cells, oligopotentcommitted progenitor cells, precursor cells, and terminallydifferentiated cells involved in hematopoiesis. Some hematologicalmalignancies are believed to arise from hematopoietic stem cells, whichhave the ability for self renewal. For instance, cells capable ofdeveloping specific subtypes of acute myeloid leukemia (AML) upontransplantation display the cell surface markers of hematopoietic stemcells, implicating hematopoietic stem cells as the source of leukemiccells. Blast cells that do not have a cell marker characteristic ofhematopoietic stem cells appear to be incapable of establishing tumorsupon transplantation (Blaire et al., 1997, Blood 89:3104-3112). The stemcell origin of certain hematological malignancies also finds support inthe observation that specific chromosomal abnormalities associated withparticular types of leukemia can be found in normal cells ofhematopoietic lineage as well as leukemic blast cells. For instance, thereciprocal translocation t(9q34; 22q11) associated with approximately95% of chronic myelogenous leukemia appears to be present in cells ofthe myeloid, erythroid, and lymphoid lineage, suggesting that thechromosomal aberration originates in hematopoietic stem cells. Asubgroup of cells in certain types of CML displays the cell markerphenotype of hematopoietic stem cells.

Although hematopoietic neoplasms often originate from stem cells,committed progenitor cells or more terminally differentiated cells of adevelopmental lineage can also be the source of some leukemias. Forexample, forced expression of the fusion protein Bcr/Abl (associatedwith chronic myelogenous leukemia) in common myeloid progenitor orgranulocyte/macrophage progenitor cells produces a leukemic-likecondition. Moreover, some chromosomal aberrations associated withsubtypes of leukemia are not found in the cell population with a markerphenotype of hematopoietic stem cells, but are found in a cellpopulation displaying markers of a more differentiated state of thehematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus,while committed progenitor cells and other differentiated cells may haveonly a limited potential for cell division, leukemic cells may haveacquired the ability to grow unregulated, in some instances mimickingthe self-renewal characteristics of hematopoietic stem cells (Passegueet al., Proc. Nall. Acad. Sci. USA, 2003, 100:11842-9).

In some embodiments, the hematopoietic neoplasm treated is a lymphoidneoplasm, where the abnormal cells are derived from and/or display thecharacteristic phenotype of cells of the lymphoid lineage. Lymphoidneoplasms can be subdivided into B-cell neoplasms, T and NK-cellneoplasms, and Hodgkin's lymphoma. B-cell neoplasms can be furthersubdivided into precursor B-cell neoplasm and mature/peripheral B-cellneoplasm. Exemplary B-cell neoplasms are precursor B-lymphoblasticleukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) whileexemplary mature/peripheral B-cell neoplasms are B-cell chroniclymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-celllymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma,extranodal marginal zone B-cell lymphoma of MALT type, nodal marginalzone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuselarge B-cell lymphoma, mediastinal large B-cell lymphoma, primaryeffusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. Thepresently disclosed compounds are particularly useful in the treatmentof T-cell and Nk-cell neoplasms, which are further subdivided intoprecursor T-cell neoplasm and mature (peripheral) T-cell neoplasms. Anexemplary precursor T-cell neoplasm is precursor T-lymphoblasticlymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia) whileexemplary mature (peripheral) T-cell neoplasms are T-cell prolymphocyticleukemia T-cell granular lymphocytic leukemia, aggressive NK-cellleukemia, adult T-cell lymphoma/leukemia (HTLV-1), extranodal NK/T-celllymphoma, nasal type, enteropathy-type T-cell lymphoma, hepatosplenicgamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-celllymphoma, Mycosis fungoides/Sezary syndrome, Anaplastic large-celllymphoma, T/null cell, primary cutaneous type, Peripheral T-celllymphoma, not otherwise characterized, Angioimmunoblastic T-celllymphoma, Anaplastic large-cell lymphoma, T/null cell, primary systemictype. The third member of lymphoid neoplasms is Hodgkin's lymphoma, alsoreferred to as Hodgkin's disease. Exemplary diagnoses of this class thatcan be treated with the compounds include, among others, nodularlymphocyte-predominant Hodgkin's lymphoma, and various classical formsof Hodgkin's disease, exemplary members of which are Nodular sclerosisHodgkin's lymphoma (grades 1 and 2), Lymphocyte-rich classical Hodgkin'slymphoma, Mixed cellularity Hodgkin's lymphoma, and Lymphocyte depletionHodgkin's lymphoma. In various embodiments, any of the lymphoidneoplasms that are associated with aberrant JAK activity can be treatedwith the JAK inhibitory compounds.

In some embodiments, the hematopoietic neoplasm treated is a myeloidneoplasm. This group includes a large class of cell proliferativedisorders involving or displaying the characteristic phenotype of thecells of the myeloid lineage. Myeloid neoplasms can be subdivided intomyeloproliferative diseases, myelodysplastic/myeloproliferativediseases, myelodysplastic syndromes, and acute myeloid leukemias.Exemplary myeloproliferative diseases are chronic myelogenous leukemia(e.g., Philadelphia chromosome positive (t(9; 22)(qq34; q11)), chronicneutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilicsyndrome, chronic idiopathic myelofibrosis, polycythemia vera, andessential thrombocythemia. Exemplary myelodysplastic/myeloproliferativediseases are chronic myelomonocytic leukemia, atypical chronicmyelogenous leukemia, and juvenile myelomonocytic leukemia. Exemplarymyelodysplastic syndromes are refractory anemia, with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome. In various embodiments, any of the myeloidneoplasms that are associated with aberrant JAK activity can be treatedwith the JAK inhibitory compounds.

In some embodiments, the JAK inhibitory compounds can be used to treatAcute myeloid leukemias (AML), which represent a large class of myeloidneoplasms having its own subdivision of disorders. These subdivisionsinclude, among others, AMLs with recurrent cytogenetic translocations,AML with multilineage dysplasia, and other AML not otherwisecategorized. Exemplary AMLs with recurrent cytogenetic translocationsinclude, among others, AML with t(8; 21)(q22; q22), AML1(CBF-alpha)/ETO,Acute promyelocytic leukemia (AML with t(15; 17)(q22; q11-12) andvariants, PML/RAR-alpha), AML with abnormal bone marrow eosinophils(inv(16)(p13q22) or t(16; 16)(p13; q11), CBFb/MYH11X), and AML with11q23 (MLL) abnormalities. Exemplary AML with multilineage dysplasia arethose that are associated with or without prior myelodysplasticsyndrome. Other acute myeloid leukemias not classified within anydefinable group include, AML minimally differentiated, AML withoutmaturation, AML with maturation, Acute myelomonocytic leukemia, Acutemonocytic leukemia, Acute erythroid leukemia, Acute megakaryocyticleukemia, Acute basophilic leukemia, and Acute panmyelosis withmyelofibrosis.

One means of assaying for such inhibition is detection of the effect ofthe 2,4-pyrimidinediamine compounds on the upregulation of downstreamgene products. In the Ramos/IL4 assay, B-cells are stimulated with thecytokine Interleukin-4 (IL-4) leading to the activation of the JAK/Statpathway through phosphorylation of the JAK family kinases, JAK1 andJAK3, which in turn phosphorylate and activate the transcription factorStat-6. One of the genes upregulated by activated Stat-6 is the lowaffinity IgE receptor, CD23. To study the effect of inhibitors (e.g.,the 2,4-substituted pyrimindinediamine compounds described herein) onthe JAK1 and JAK3 kinases, human Ramos B cells are stimulated with humanIL-4. 20 to 24 hours post stimulation, cells are stained forupregulation of CD23 and analyzed using FACS. A reduction of the amountof CD23 present compared to control conditions indicates the testcompound actively inhibits the JAK kinase pathway. An exemplary assay ofthis type is described in greater detail in Example 2.

The activity of the compounds described herein can further becharacterized by assaying the effect of the 2,4-pyrimidinediaminecompounds described herein on the proliferative response of primaryhuman T-cells. In this assay, primary human T-cells derived fromperipheral blood and pre-activated through stimulation of the T-cellreceptor and CD28, proliferate in culture in response to the cytokineInterleukin-2 (IL-2). This proliferative response is dependent on theactivation of JAK1 and JAK3 tyrosine kinases, which phosphorylate andactivate the transcription factor Stat-5. The primary human T-cells areincubated with the 2,4-pyrimidinediamine compounds in the presence ofIL-2 for 72 hours, and at the assay endpoint intracellular ATPconcentrations are measured to assess cell viability. A reduction incell proliferation compared to control conditions is indicative ofinhibition of the JAK kinase pathway.

The activity of the compounds described herein can additionally becharacterized by assaying the effect of the 2,4-pyrimidinediaminecompounds described herein on A549 lung epithelial cells and U937 cells.A549 lung epithelial cells and U937 cells up-regulate ICAM-1 (CD54)surface expression in response to a variety of different stimuli.Therefore, using ICAM-1 expression as readout, test compound effects ondifferent signaling pathways can be assessed in the same cell type.Stimulation with IL-1β through the IL-1β receptor activates theTRAF6/NFκB pathway resulting in up-regulation of ICAM-1. IFNγ inducesICAM-1 up-regulation through activation of the JAK1/JAK2 pathway. Theup-regulation of ICAM-1 can be quantified by flow cytometry across acompound dose curve and EC₅₀ values are calculated.

Active compounds as described herein generally inhibit the JAK kinasepathway with an IC₅₀ in the range of about 1 mM or less, as measured inthe assays described herein. Of course, skilled artisans will appreciatethat compounds which exhibit lower IC₅₀s, (on the order, for example, of100 μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM, 15 μM, 10 μM, 5 μM, 11 μM,500 nM, 100 nM, 10 nM, 1 nM, or even lower) can be particularly usefulin therapeutic applications. In instances where activity specific to aparticular cell type is desired, the compound can be assayed foractivity with the desired cell type and counter-screened for a lack ofactivity against other cell types. The desired degree of “inactivity” insuch counter screens, or the desired ratio of activity vs. inactivity,may vary for different situations and can be selected by the user.

The 2,4-pyrimidinediamine active compounds also typically inhibit IL-4stimulated expression of CD23 in B-cells with an IC₅₀ in the range ofabout 20 μM or less, typically in the range of about 10 μM, 500 nM, 100nM, 10 nM, 1 nM, or even lower. A suitable assay that can be used is theassay described in Example 2, “Assay for Ramos B-Cell Line Stimulatedwith IL-4.” In certain embodiments, the active 2,4-pyrimidinediaminecompounds have an IC₅₀ of less than or equal to 5 μM, greater than 5 μMbut less than 20 μM, greater than 20 μM, or greater than 20 μM but lessthan 50 μM in the assay described in Example 2.

Additionally, the 2,4-pyrimidinediamine active compounds typicallyinhibit an activity of human primary T-cells with an IC₅₀ in the rangeof about 20 μM or less, typically in the range of about 10 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower. The IC₅₀ against human primaryT-cells can be determined in a standard in vitro assay with isolatedhuman primary T-cells. A suitable assay that can be used is the assaydescribed above, “Primary Human T-cell Proliferation Assay Stimulatedwith IL-2.” In some embodiments, the active 2,4-pyrimidinediaminecompounds have an IC₅₀ of less than or equal to 5 μM, greater than 5 μMbut less than 20 μM, greater than 20 μM, or greater than 20 μM but lessthan 50 μM in the assay described above.

The 2,4-pyrimidinediamine active compounds also typically inhibitexpression of ICAM1 (CD54) induced by IFNγ exposure in U937 or A549cells with an IC₅₀ in the range of about 20 μM or less, typically in therange of about 10 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. TheIC₅₀ against expression of ICAM (CD54) in IFNγ stimulated cells can bedetermined in a functional cellular assay with an isolated A549 or U937cell line. The active 2,4-pyrimidinediamine compounds typically have anIC₅₀ of less than or equal to 20 μM, greater than 20 μM, or greater than20 μM but less than 50 μM in the assay.

Utility of the Compounds as Research Tools

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particular JAK-ligandcomplexes, and their corresponding X-ray structure coordinates can beused to reveal new structural information useful for understanding thebiological activity of kinases as described herein. As well, the keystructural features of the aforementioned proteins, particularly, theshape of the ligand binding site, are useful in methods for designing oridentifying selective modulators of kinases and in solving thestructures of other proteins with similar features. Such protein-ligandcomplexes, having compounds described herein as their ligand component,are an aspect of the invention.

As well, one of ordinary skill in the art would appreciate that suchsuitable X-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of kinases. Such methods can be characterized by the followingaspects: a) introducing into a suitable computer program, informationdefining a ligand binding domain of a kinase in a conformation (e.g. asdefined by X-ray structure coordinates obtained from suitable X-rayquality crystals as described above) where the computer program createsa model of the three dimensional structures of the ligand bindingdomain, b) introducing a model of the three dimensional structure of acandidate agent in the computer program, c) superimposing the model ofthe candidate agent on the model of the ligand binding domain, and d)assessing whether the candidate agent model fits spatially into theligand binding domain. Aspects a-d are not necessarily carried out inthe aforementioned order. Such methods can further entail: performingrational drug design with the model of the three-dimensional structure,and selecting a potential candidate agent in conjunction with computermodeling.

Additionally, one skilled in the art would appreciate that such methodscan further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods can also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds describedherein can be used in a method of evaluating the ability of a test agentto associate with a molecule or molecular complex including a ligandbinding domain of a kinase. Such a method can be characterized by thefollowing aspects: a) creating a computer model of a kinase bindingpocket using structure coordinates obtained from suitable X-ray qualitycrystals of the kinase, b) employing computational algorithms to performa fitting operation between the test agent and the computer model of thebinding pocket, and c) analyzing the results of the fitting operation toquantify the association between the test agent and the computer modelof the binding pocket.

Utility of the Compounds as Screening Agents

To employ the compounds described herein in a method of screening forcandidate agents that bind to, for example a JAK protein, the protein isbound to a support, and a compound described herein is added to theassay. Alternatively, the compound described herein is bound to thesupport, e.g. via a linker that does not prohibitively affect biologicalactivity, and the protein is added. Classes of candidate agents amongwhich novel binding agents can be sought include specific antibodies,non-natural binding agents identified in screens of chemical libraries,peptide analogs, etc. Of particular interest are screening assays forcandidate agents that have a low toxicity for human cells. A widevariety of assays can be used for this purpose, including labeled invitro protein-protein binding assays, electrophoretic mobility shiftassays, immunoassays for protein binding, functional assays(phosphorylation assays, etc.) and the like.

The determination of the binding of the candidate agent to, for example,a JAK protein can be done in a number of ways. In one example, thecandidate agent (the compound described herein) is labeled, for example,with a fluorescent or radioactive moiety and binding determineddirectly. For example, this can be done by attaching all or a portion ofthe JAK protein to a solid support, adding a labeled agent (for examplea compound described herein in which at least one atom has been replacedby a detectable isotope), washing off excess reagent, and determiningwhether the amount of the label is that present on the solid support.Various blocking and washing steps can be utilized as is known in theart. “Labeled” means that the compound is either directly or indirectlylabeled with something which provides a detectable signal, e.g.,radioisotope, fluorescent tag, enzyme, antibodies, particles such asmagnetic particles, chemiluminescent tag, or specific binding molecules,etc. Specific binding molecules include pairs, such as biotin andstreptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

In some embodiments, only one of the components is labeled. For example,a JAK protein can be labeled at tyrosine positions using ¹²⁵I, or withfluorophores. Alternatively, more than one component can be labeled withdifferent labels; using ¹²⁵I for the proteins, for example, and afluorophore for the candidate agents.

The compounds described herein can also be used as competitors to screenfor additional drug candidates. “Candidate bioactive agent” or “drugcandidate” or grammatical equivalents as used herein describe anymolecule, e.g., protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. In the case where protein binding oractivity is screened, some embodiments exclude molecules already knownto bind to that particular protein. Exemplary embodiments of assaysdescribed herein include candidate agents, which do not bind the targetprotein in its endogenous native state, termed herein as “exogenous”agents. In one example, exogenous agents further exclude antibodies toJAK proteins.

Candidate agents can encompass numerous chemical classes, thoughtypically they are organic molecules having a molecular weight of morethan about 100 daltons and less than about 2,500 daltons. Candidateagents include functional groups necessary for structural interactionwith proteins, particularly hydrogen bonding and lipophilic binding, andtypically include at least an amine, carbonyl, hydroxyl, ether, orcarboxyl group, for example at least two of the functional chemicalgroups. The candidate agents often include cyclical carbon orheterocyclyl structures and/or aromatic or polyaromatic structuressubstituted with one or more of the above functional groups. Candidateagents are also found among biomolecules including peptides,saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,structural analogs, or combinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentscan be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification to producestructural analogs.

In one example, the binding of the candidate agent is determined throughthe use of competitive binding assays. In this example, the competitoris a binding moiety known to bind to a JAK protein, such as an antibody,peptide, binding partner, ligand, etc. Under certain circumstances,there may be competitive binding as between the candidate agent and thebinding moiety, with the binding moiety displacing the candidate agent.

In some embodiments, the candidate agent is labeled. Either thecandidate agent, or the competitor, or both, is added first to forexample a JAK protein for a time sufficient to allow binding, ifpresent. Incubations can be performed at any temperature thatfacilitates optimal activity, typically between 4° C. and 40° C.Incubation periods are selected for optimum activity, but can also beoptimized to facilitate rapid high throughput screening. Excess reagentis generally removed or washed away. The second component is then added,and the presence or absence of the labeled component is followed, toindicate binding.

In one example, the competitor is added first, followed by the candidateagent.

Displacement of the competitor is an indication the candidate agent isbinding to a JAK protein and thus is capable of binding to, andpotentially modulating, the activity of the JAK protein. In thisembodiment, either component can be labeled. Thus, for example, if thecompetitor is labeled, the presence of label in the wash solutionindicates displacement by the agent. Alternatively, if the candidateagent is labeled, the presence of the label on the support indicatesdisplacement.

In an alternative embodiment, the candidate agent is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor may indicate the candidate agent is bound to aJAK protein with a higher affinity. Thus, if the candidate agent islabeled, the presence of the label on the support, coupled with a lackof competitor binding, may indicate the candidate agent is capable ofbinding to the JAK protein.

It may be of value to identify the binding site of a JAK protein. Thiscan be done in a variety of ways. In one embodiment, once the JAKprotein has been identified as binding to the candidate agent, the JAKprotein is fragmented or modified and the assays repeated to identifythe necessary components for binding.

Modulation is tested by screening for candidate agents capable ofmodulating the activity of a JAK protein including the steps ofcombining a candidate agent with the JAK protein, as above, anddetermining an alteration in the biological activity of the JAK protein.Thus, in this embodiment, the candidate agent should both bind to(although this may not be necessary), and alter its biological orbiochemical activity as defined herein. The methods include both invitro screening methods and in vivo screening of cells for alterationsin cell viability, morphology, and the like.

Alternatively, differential screening can be used to identify drugcandidates that bind to a native JAK protein, but cannot bind to amodified JAK protein.

A variety of other reagents can be included in the screening assays.These include reagents like salts, neutral proteins, e.g., albumin,detergents, etc which can be used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,can be used. The mixture of components can be added in any order thatprovides for the requisite binding.

Methods of Administration

The 2,4-pyrimidinediamine compound(s) or prodrug(s) described herein, orcompositions thereof, will generally be used in an amount effective toachieve the intended result, for example, in an amount effective totreat or prevent the particular condition being treated. The compound(s)can be administered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmatic attackor a reduction in the frequency or severity of asthmatic episodes. Asanother specific example, therapeutic benefit in the context oftransplantation rejection includes the ability to alleviate an acuterejection episode, such as, for example, HVGR or GVHR, or the ability toprolong the time period between onset of acute rejection episodes and/oronset of chronic rejection. Therapeutic benefit also includes halting orslowing the progression of the disease, regardless of whetherimprovement is realized.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular condition being treated,the mode of administration, the severity of the condition being treated,the age and weight of the patient, the bioavailability of the particularactive compound. Determination of an effective dosage is well within thecapabilities of those skilled in the art.

As known by those of skill in the art, the preferred dosage of2,4-pyrimidinediamine compounds will also depend on the age, weight,general health, and severity of the condition of the individual beingtreated. Dosage may also need to be tailored to the sex of theindividual and/or the lung capacity of the individual, whereadministered by inhalation. Dosage may also be tailored to individualssuffering from more than one condition or those individuals who haveadditional conditions which affect lung capacity and the ability tobreathe normally, for example, emphysema, bronchitis, pneumonia, andrespiratory infections. Dosage, and frequency of administration of thecompounds or prodrugs thereof, will also depend on whether the compoundsare formulated for treatment of acute episodes of a condition or for theprophylactic treatment of a disorder. For example, acute episodes ofallergic conditions, including allergy-related asthma, transplantrejection, etc. A skilled practitioner will be able to determine theoptimal dose for a particular individual.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient is allergicto a particular drug, the compound can be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration can be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound can be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundscan also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundcan be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound can be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

In the context of transplant rejection, the compound can be administeredwhile the patient is not having an acute rejection reaction to avoid theonset of rejection and/or prior to the appearance of clinicalindications of chronic rejection. The compound can be administeredsystemically to the patient as well as administered to the tissue ororgan prior to transplanting the tissue or organ in the patient.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, and the bioavailabilityof the particular active compound. Determination of an effective dosageis well within the capabilities of those skilled in the art.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in anin vitro assay. Calculating dosages to achieve such circulating blood orserum concentrations taking into account the bioavailability of theparticular compound is well within the capabilities of skilled artisans.For guidance, the reader is referred to Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, andthe references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Suitable animal models of allergic conjunctivitis are described inCarreras et al., (1993), Br. J. Ophthalmol. 77(8):509-514; Saiga et al.,(1992), Ophthalmic Res. 24(1):45-50; and Kunert et al., (2001), Invest.Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models ofsystemic mastocytosis are described in O'Keefe et al., (1987), J. Vet.Intern. Med. 1(2):75-80 and Bean-Knudsen et al., (1989), Vet. Pathol.26(1):90-92. Suitable animal models of hyper IgE syndrome are describedin Claman et al., (1990), Clin. Immunol. Immunopathol. 56(1):46-53.Suitable animal models of B-cell lymphoma are described in Hough et al.,(1998), Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et al.,(1996), J. Immunol. 157(12):5503-5511. Suitable animal models of atopicdisorders such as atopic dermatitis, atopic eczema, and atopic asthmaare described in Chan et al., (2001), J. Invest. Dermatol.117(4):977-983 and Suto et al., (1999), Int. Arch. Allergy Immunol.120(Suppl 1):70-75. Suitable animal models of transplant rejection, suchas models of HVGR, are described in O'Shea et al., (2004), NatureReviews Drug Discovery 3:555-564; Cetkovic-Curlje & Tibbles, (2004),Current Pharmaceutical Design 10:1767-1784; and Chengelian et al.,(2003), Science 302:875-878. Ordinarily skilled artisans can routinelyadapt such information to determine dosages suitable for humanadministration.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration, and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds can be administered once per week, several times per week(e.g., every other day), once per day, or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated, and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The foregoing disclosure pertaining to the dosage requirements for the2,4-sbustituted pyrimidinediamine compounds is pertinent to dosagesrequired for prodrugs, with the realization, apparent to the skilledartisan, that the amount of prodrug(s) administered will also dependupon a variety of factors, including, for example, the bioavailabilityof the particular prodrug(s) and the conversation rate and efficiencyinto active drug compound under the selected route of administration.Determination of an effective dosage of prodrug(s) for a particular useand mode of administration is well within the capabilities of thoseskilled in the art.

Effective dosages can be estimated initially from in vitro activity andmetabolism assays. For example, an initial dosage of prodrug for use inanimals can be formulated to achieve a circulating blood or serumconcentration of the metabolite active compound that is at or above anIC₅₀ of the particular compound as measured in an in vitro assay, suchas the in vitro CHMC or BMMC and other in vitro assays described in U.S.application Ser. No. 10/355,543 filed Jan. 31, 2003 (US2004/0029902A1),international application Serial No. PCT/US03/03022 filed Jan. 31, 2003(WO 03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29,2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. application Ser. No. 10/903,263 filed Jul. 30,2004, and international application Serial No. PCT/US2004/24716(WO005/016893). Calculating dosages to achieve such circulating blood orserum concentrations, taking into account the bioavailability of theparticular prodrug via the desired route of administration, is wellwithin the capabilities of skilled artisans. For guidance, the reader isreferred to Fingl & Woodbury, “General Principles,” In: Goodman andGilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46,latest edition, Pagamonon Press, and the references cited therein.

Also provided are kits for administration of the 2,4-pyrimidinediamine,prodrug thereof, or pharmaceutical formulations including the compoundthat may include a dosage amount of at least one 2,4-pyrimidinediamineor a composition including at least one 2,4-pyrimidinediamine, asdisclosed herein. Kits can further include suitable packaging and/orinstructions for use of the compound. Kits can also include a means forthe delivery of the at least one 2,4-pyrimidinediamine or compositionsincluding at least one 2,4-pyrimidinediamine, such as an inhaler, spraydispenser (e.g., nasal spray), syringe for injection, or pressure packfor capsules, tables, suppositories, or other device as describedherein. A kit can also provide the compound and reagents to prepare acomposition for administration. The composition can be in a dry orlyophilized form or in a solution, particularly a sterile solution. Whenthe composition is in a dry form, the reagent can include apharmaceutically acceptable diluent for preparing a liquid formulation.The kit can contain a device for administration or for dispensing thecompositions, including, but not limited to, syringe, pipette,transdermal patch, or inhalant.

The kits can include other therapeutic compounds for use in conjunctionwith the compounds described herein. In one embodiment, the therapeuticagents are immunosuppressant or anti-allergen compounds. These compoundscan be provided in a separate form or mixed with the compounds of thepresent invention.

The kits will include appropriate instructions for preparation andadministration of the composition, side effects of the compositions, andany other relevant information. The instructions can be in any suitableformat, including, but not limited to, printed matter, videotape,computer readable disk or optical disc.

One embodiment is a kit including a compound of formula I, or a prodrugthereof, packaging, and instructions for use.

In another embodiment, this invention provides a kit including thepharmaceutical formulation including a compound of formula I or aprodrug thereof and at least one pharmaceutically acceptable excipient,diluent, preservative, stabilizer, or mixture thereof, packaging, andinstructions for use.

Another embodiment is a kit for treating an individual who suffers fromor is susceptible to the conditions described herein are provided,including a container including a dosage amount of an2,4-pyrimidinediamine or composition, as disclosed herein, andinstructions for use. The container can be any of those known in the artand appropriate for storage and delivery of oral, intravenous, topical,rectal, urethral, or inhaled formulations.

Kits can also be provided that contain sufficient dosages of the2,4-pyrimidinediamine or composition to provide effective treatment foran individual for an extended period, such as a week, 2 weeks, 3, weeks,4 weeks, 6 weeks, or 8 weeks or more.

It will be appreciated by one of skill in the art that the embodimentssummarized above can be used together in any suitable combination togenerate additional embodiments not expressly recited above, and thatsuch embodiments are considered to be part of the present invention.

Synthesis of Compounds

The 2,4-pyrimidinediamine compounds described herein can be synthesizedvia a variety of different synthetic routes using commercially availablestarting materials and/or starting materials prepared by conventionalsynthetic methods. Suitable exemplary methods that can be routinelyadapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugsdescribed herein are found in U.S. Pat. No. 5,958,935, the disclosure ofwhich is incorporated herein by reference. Specific examples describingthe synthesis of numerous 2,4-pyrimidinediamine compounds and prodrugs,as well as intermediates therefore, are described in U.S. applicationSer. No. 10/355,543, filed Jan. 31, 2003 (US2004/0029902A1), thecontents of which are incorporated herein by reference. Suitableexemplary methods that can be routinely used and/or adapted tosynthesize active 2,4-substituted pyrimidinediamine compounds can alsobe found in international application Serial No. PCT/US03/03022 filedJan. 31, 2003 (WO 03/063794), U.S. application Ser. No. 10/631,029 filedJul. 29, 2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. application Ser. No. 10/903,263 filed Jul. 30,2004, and international application Serial No. PCT/US2004/24716(WO005/016893), the disclosures of which are incorporated herein byreference. All of the compounds described herein (including prodrugs)can be prepared by routine adaptation of these methods.

Specific exemplary synthetic methods for the 2,4-substitutedpyrimidinediamines described herein are also described in Example 1,below. Those of skill in the art will also be able to readily adaptthese examples for the synthesis of additional 2,4-substitutedpyrimidinediamines as described herein.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds described herein are depicted inSchemes (I)-(VII), below. These methods can be routinely adapted tosynthesize the 2,4-substituted pyrimidinediamine compounds describedherein. After each reaction step, the product can be purified or can,depending on the chemistry, be used in the next step withoutpurification.

For example, the compounds can be synthesized from substituted orunsubstituted uracils as illustrated in Scheme (I), below. In Scheme(I), ring A, R⁵, (R²)_(p), X, Y, Z¹, and Z² are as defined herein.According to Scheme (I), uracil A-1 is dihalogenated at the 2- and4-positions using a standard halogenating agent such as POCl₃ (or otherstandard halogenating agent) under standard conditions to yield2,4-dichloropyrimidine A-2. Depending upon the R⁵ substituent, inpyrimidinediamine A-2, the chloride at the C4 position is more reactivetowards nucleophiles than the chloride at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines I by first reacting 2,4-dichloropyrimidine A-2with one equivalent of amine A-3, yielding4N-substituted-2-chloro-4-pyrimidineamine A-4, followed by amine A-5 toyield a 2,4-pyrimidinediamine of formula A-6 (compounds of formula I,where each of R³ and R⁴ are H). Compounds of formula I, where either orboth of the NH groups at C2 and C4 of the pyrimidine are substituted,can be made, e.g., via alkylation of the NH groups.

Typically, the C4 halide is more reactive towards nucleophiles, asillustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the R⁵ substituent may alter this reactivity.For example, when R⁵ is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine A-4 and the corresponding2N-substituted-2-pyrimidineamine is obtained. The regioselectivity ofthe reaction can also be controlled by adjusting the solvent and othersynthetic conditions (such as temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions can be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry, Uppsala,Sweden) in a sealed tube (at 20 bar pressure).

The uracil A-1 starting materials can be purchased from commercialsources or prepared using standard techniques of organic chemistry.Commercially available uracils that can be used as starting materials inScheme (I) include, by way of example and not limitation, uracil(Aldrich #13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich#85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CASRegistry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5);5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6).Additional 5-substituted uracils are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif. and/or Interchim, Cedex,France, or can be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Amines A-3 and A-5 can be purchased from commercial sources or,alternatively, can be synthesized utilizing standard techniques. Forexample, suitable amines can be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines A-3 andA-5 and/or substituent X on uracil A-1 can include functional groupsthat require protection during synthesis. The exact identity of anyprotecting group(s) used will depend upon the identity of the functionalgroup being protected, and will be apparent to those of skill in theart. Guidance for selecting appropriate protecting groups, as well assynthetic strategies for their attachment and removal, can be found, forexample, in Green & Wuts.

Thus, protecting group refers to a group of atoms that, when attached toa reactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group can beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Green & Wuts and inHarrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8,1971-1996, John Wiley & Sons, NY. Representative amino protecting groupsinclude, but are not limited to, formyl, acetyl, trifluoroacetyl,benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”),trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityland substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxylprotecting groups include,but are not limited to, those where the hydroxyl group is eitheracylated to form acetate and benzoate esters or alkylated to form benzyland trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers,trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.

A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich#32, 937-1) as a starting material is illustrated in Scheme (Ia), below.In Scheme (Ia), ring A, (R²)_(p), X, Y, Z¹, and Z² are as previouslydefined for Scheme (I). Compound A-10, a2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine, can be obtained byreacting 2,4-dichloro-5-fluoropyrimidine A-8 (commercially available ormade from A-7 as depicted e.g. starting with a uracil anddehydrohalogenating with e.g. POCl₃) with, optimally, one equivalent ofamine A-3 to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamineA-9 followed by reaction with one or more equivalents of amine A-5,typically between about 1.1 equivalents of A-5 and about 2 equivalentsof A-5.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances certain substituents, such as, for example, R² and/orother groups, can include functionality requiring protection. The exactidentity of the protecting group used will depend upon, among otherthings, the identity of the functional group being protected and thereaction conditions used in the particular synthetic scheme, and will beapparent to those of skill in the art. Guidance for selecting protectinggroups, their attachment and removal suitable for a particularapplication can be found, for example, in Green & Wuts.

Prodrugs as described herein can be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs can beprepared by reacting a suitably protected 2,4-pyrimidinediamine with asuitable reagent to append the desired progroup. Conditions for carryingout such reactions and for deprotecting the product to yield a prodrugas described herein are well-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(VII),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV″); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

EXAMPLES

The invention is further understood by reference to the followingexamples, which are not intended to be limiting. Any synthetic methodsthat are functionally equivalent are within the scope of the invention.Various modifications of the embodiments described herein would beapparent to one of ordinary skill in the art from the foregoingdescription and accompanying figures. Such modifications fall within thescope of the appended claims.

One embodiment of the invention is a compound, according to formula I,as described in the examples below.

In the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

TFA = trifluoroacetic acid mmol = millimole MeOH = methanol nM =nanomolar ETOAc = ethyl acetate DMSO = dimethylsulfoxide i-PrOH =isopropanol mL or ml = milliliter EtOH = ethanol mg = milligram s =singlet psi = pounds per inches² d = doublet N = normal t = triplet μM =micromolar q = quartet rpm = revolutions/minute m = multiplet rt = roomtemperature dd = doublet of doublets aq. = aqueous br = broad μL =microliter MS = mass spectrum FBS = fetal bovine serum MS (ES)= massspectrometry liquid (electrospray) LCMS = chromatography RP-HPLC =reverse phase high mass spectrometer pressure liquid FACS = flowcytometry chromatography

Example 1 Synthesis of pyrimidine-2,4-diamines Synthesis of5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

To a vial with 5-aminobenzo[d]oxazol-2(3H)-one (300.1 mg, 2.0 mmol) and2,4-dichloro-5-methylpyrimidine (423.8 mg, 2.6 mmol), MeOH (8 mL) andH₂O (2 mL) were added. The turbid mixture was stirred at roomtemperature for 64 h. Precipitate from reaction mixture was collected byfiltration, washing with EtOAc (3 mL×2), and was further dried in vacuo.5-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one wasobtained as an off-white solid: 394 mg (71% yield); ¹H NMR (300 MHz,DMSO) δ 11.68 (br s, 1H), 8.62 (s, 1H), 7.94 (d, J=0.8, 1H), 6.97 (d,J=2.0, 1H), 6.82 (d, J=8.1, 1H), 6.74 (dd, J=2.0, 8.1, 1H), 2.15 (s,3H); LCMS (M+) m/z 277.10.

Synthesis ofN4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine:(I-16)

To a vial with5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (138.3mg, 0.5 mmol) and 3-(methylsulfonyl)benzenamine hydrochloride (207.7 mg,1.0 mmol), i-PrOH (10 mL) was added, followed by TFA (116 μL, 1.5 mmol).The vial was tightly closed, and the reaction mixture was stirred at85-90° C. for 40 h. The solvent was removed in vacuo, and the crudeproduct was purified by RP-HPLC.N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diaminewas obtained as a mono-trifluoroacetate salt: an off-white solid, 129 mg(49% yield); ¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.43 (s, 1H), 8.43(s, 1H), 8.20 (s, 1H), 8.11 (br d, J=7.5, 1H), 7.96 (d, J=0.8, 1H),7.49-7.33 (m, 4H), 7.27 (d, J=8.5, 1H), 3.13 (s, 3H), 2.16 (s, 3H); LCMS(M+) m/z 412.47.

Synthesis of5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one

To a vial with 5-amino-1H-benzo[d]imidazol-2(3H)-one (298.3 mg, 2.0mmol) and 2,4-dichloro-5-fluoropyrimidine (434.1 mg, 2.6 mmol), MeOH (8mL) and H₂O (2 mL) were added. The turbid solution was stirred at rt for3 days. Precipitate from reaction mixture was collected by filtration,and washing with EtOAc (3 mL×2), and was further dried in vacuo.5-(2-Chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-onewas obtained as an off-white solid: 390.3 mg (70% yield); ¹H NMR (300MHz, DMSO) δ 10.69 (s, 1H), 10.63 (s, 1H), 9.87 (s, 1H), 8.27 (d, J=3.6,1H), 7.35 (d, J=1.9, 1H), 7.18 (dd, J=1.9, 8.3, 1H), 6.93 (d, J=8.3,1H); LCMS (M⁺) m/z 279.80.

Synthesis of 4-(5-nitropyridin-2-yl)morpholine

In a round-bottom flask, to a dichloromethane (125 mL) solution of2-bromo-5-nitropyridine (5 g, 24.6 mmol), morpholine (5.4 mL, 61.5 mmol)was added. The reaction was refluxed for 4 hr, then cooled to roomtemperature. The solution was subsequently washed with saturated aqueoussodium bicarbonate solution and brine. The organic layer was dried(Na₂SO₄), filtered, and the solvent was removed in vacuo.4-(5-Nitropyridin-2-yl)morpholine, a yellow solid, was obtained: 4.9 g(95% yield); ¹H NMR (300 MHz, DMSO) δ 8.95 (d, J=2.7, 1H), 8.22 (dd,J=2.7, 9.6, 1H), 6.92 (d, J=9.6, 1H), 3.74-3.65 (m, 8H); LCMS (M+) m/z210.34.

Synthesis of 6-morpholinopyridin-3-amine

Into a EtOH (250 mL) solution of 4-(5-nitropyridin-2-yl)morpholine (4.9g, 23.4 mmol), 10% Pd on activated carbon, 500 mg, was added.Hydrogenation was carried out in a Parr flask at room temperature, at 40psi for 2 hr. The solids were filtered off and the filtrate wascollected. The solvent was removed in vacuo.6-Morpholinopyridin-3-amine, as a purple solid, was obtained: 3.7 g (88%yield); ¹H NMR (300 MHz, DMSO) δ 7.64 (d, J=2.7, 1H), 6.96 (dd, J=2.7,8.8, 1H), 6.65 (d, J=8.8, 1H), 4.63 (s, 2H), 3.72-3.69 (m, 4H),3.21-3.18 (m, 4H); LCMS (M+) m/z 180.08.

Synthesis ofN4-(benzimidazolin-2-on-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-fluoropyrimidine-2,4-diamine:(II-19)

To a vial with5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one(27.6 mg, 0.1 mmol) and 6-morpholinopyridin-3-amine (35.8 mg, 0.2 mmol),i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vialwas tightly closed, and the turbid solution was stirred at 95° C. for 2days. The solvent was removed in vacuo, and the crude product waspurified by RP-HPLC.N4-(Benzimidazolin-2-on-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-fluoropyrimidine-2,4-diaminewas obtained as a light orange solid, as a di-trifluoroacetate salt:51.1 mg (79% yield); ¹H NMR (300 MHz, DMSO) δ 10.61 (s, 2H), 9.79 (br s,1H), 9.55 (br s, 1H), 8.31 (s, 1H), 8.13 (d, J=4.4, 1H), 7.92 (br d,J=8.8, 1H), 7.22 (d, J=8.1, 1H), 7.18 (s, 1H), 7.10 (br d, J=8.8, 1H),6.89 (d, J=8.1, 1H), 3.78-3.75 (m, 4H), 3.50-3.47 (m, 4H); LCMS (M+) m/z423.00.

Synthesis of6-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

To a vial with 6-aminobenzo[d]oxazol-2(3H)-one (1.0 g, 6.7 mmol) and2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol), solvents MeOH (20 mL)and H₂O (5 mL) were added. The turbid mixture was stirred at roomtemperature for 2 days. Precipitate from the reaction mixture wascollected by filtration, washing with H₂O (3 mL×2) and EtOAc (3 mL×2),and was further drying in vacuo.6-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one wasobtained as a light tan color solid: 1.59 g (86% yield); ¹H NMR (300MHz, DMSO) δ 11.59 (s, 1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H),7.28 (d, J=8.3, 1H), 7.06 (d, J=8.3, 1H), 2.14 (s, 3H).

Synthesis ofN4-(benzo[d]oxazol-2(3H)-on-6-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine:(I-48)

To a vial with6-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7mg, 0.1 mmol) and 3-morpholinobenzenamine (26.7 mg, 0.15 mmol), i-PrOH(2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial wastightly closed, and the solution was stirred at 95° C. for 2 days. Thesolvent was removed in vacuo, and the crude product was purified byRP-HPLC.N4-(benzo[d]oxazol-2(3H)-on-6-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diaminewas obtained as a light tan color solid: 32.9 mg (78% yield); ¹H NMR(300 MHz, DMSO) δ 11.57 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.90 (s,1H), 7.81 (s, 1H), 7.37 (d, J=8.3, 1H), 7.27 (s, 1H), 7.14 (d, J=8.3,1H), 7.07-7.01 (m, 2H), 6.58-6.50 (m, 1H), 3.68-3.65 (m, 4H), 2.95-2.92(m, 4H), 2.14 (s, 3H); LCMS (M+) m/z 419.03.

Synthesis ofN4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine:(II-13)

To a vial with5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg,1.0 mmol), PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol).The vial was tightly closed, and the reaction mixture was stirred at 85°C. for 2 days. The solvents were removed in vacuo, and the crude productwas purified by RP-HPLC. Purified compound (as a trifluoroacetate salt)was dissolved in MeOH—H₂O (1:4, 2 mL) and was passed through aPL-HCO₃-MP-SPE column, washing with same solvents (1 mL). The filtratewas collected and the solvent was removed by lyophilization.N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diaminewas obtained as a purple solid, 23.1 mg (53% yield); ¹H NMR (300 MHz,DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m,2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H),3.40-3.37 (m, 4H, overlapped with H₂O), 2.44-2.41 (m, 4H), 2.25 (s, 3H),2.11 (s, 3H); LCMS (M+) m/z 433.52.

Synthesis ofN4-(benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine:(II-16)

To a vial with5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one(28.0 mg, 0.1 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4mg, 0.2 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13mmol). The vial was tightly closed, and the solution was stirred at 85°C. for 2 days. The solvent was removed in vacuo, and the crude productwas purified by RP-HPLC. Purified compound (as a trifluoroacetate salt)was dissolved in MeOH—H₂O (1:4, 2 mL) and was passed through aPL-HCO₃-MP-SPE column, washing with same solvents (1 mL). The filtratewas collected and the solvent was removed by lyophilization.N4-(Benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diaminewas obtained as a purple solid: 26.2 mg (60% yield); ¹H NMR (300 MHz,DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27(br d, J=2.3, 1H), 8.00 (br d, J=3.8, 1H), 7.84 (dd, J=2.3, 9.1, 1H),7.30 (dd, J=1.7, 8.2, 1H), 7.17 (d, J=1.7, 1H), 6.86 (d, J=8.2, 1H),6.73 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H₂O), 2.44-2.41(m, 4H), 2.25 (s, 3H); LCMS (M+) m/z 436.50.

Synthesis of6-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one:(II-25)

To a vial with5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one(28.0 mg, 0.1 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4mg, 0.2 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13mmol). The vial was tightly closed, and the solution was stirred at 85°C. for 2 days. The solvent was removed in vacuo, and the crude productwas purified by RP-HPLC. Purified compound (as a trifluoroacetate salt)was dissolved in MeOH—H₂O (1:4, 2 mL) and was passed through aPL-HCO₃-MP-SPE column, washing with same solvents (1 mL). The filtratewas collected and the solvent was removed by lyophilization.6-(5-Methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-onewas obtained as a purple solid: 26.2 mg (60% yield); ¹H NMR (300 MHz,DMSO) δ 11.70 (s, 1H), 9.97 (s, 1H), 9.49 (s, 1H), 8.15 (s, 1H), 7.82(s, 1H), 7.65 (d, J=11.7, 2H), 7.21 (d, J=8.8, 1H), 7.05 (d, J=8.4, 1H),6.89 (d, J=8.9, 1H), 4.34-4.31 (m, 4H), 3.09-3.07 (m, 4H), 2.85 (s, 3H),2.13 (s, 3H).

The following compounds were made in a similar fashion to the aboveexamples or by methods described herein or known to skilled artisans.

I-1:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-formylphenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 363.02 (M+H), 361.18 (M−H); ¹H NMR (300 MHz, DMSO) δ 10.47 (s,1H), 9.75 (s, 1H), 7.94 (t, J=6.3, 2H), 7.70 (m, 3H), 7.55 (d, J=7.5,1H), 7.41 (d, J=7.9, 3H), 7.24 (t, J=7.9, 1H), 2.16 (s, 3H) ppm.

I-2:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-aminocarbonylphenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 376.99 (M+H), 375.11 (M−H); ¹H NMR (300 MHz, DMSO) δ 11.66 (s,1H), 10.36 (s, 1H), 9.61 (s, 1H), 7.93 (m, 2H), 7.76 (s, 1H), 7.63 (d,J=7.9, 1H), 7.54 (d, J=7.6, 1H), 7.42 (m, 1H), 7.25 (dd, J=7.4, 14.7,1H), 2.14 (s, 3H) ppm.

I-3:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-aminocarbonylphenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 377.12 (M+H), 375.04 (M−H); ¹H NMR (300 MHz, DMSO) δ 11.78 (s,1H), 10.40 (s, 1H), 9.61 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.70 (d,J=8.6, 2H), 7.51 (d, J=8.6, 2H), 7.33 (s, 1H), 2.14 (s, 3H) ppm.

I-4:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-formylphenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 363.02 (M+H), 361.01 (M−H); ¹H NMR (300 MHz, DMSO) δ 10.27 (s,1H), 9.43 (s, 1H), 8.04-7.85 (m, 2H), 7.73 (t, J=9.6, 1H), 7.57 (d,J=8.7, 2H), 7.31 (s, 1H), 7.24 (s, 1H), 2.16 (s, 3H) ppm.

I-5:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 514.25 (M+H), 512.32 (M−H); ¹H NMR (300 MHz, DMSO) δ 8.92 (s,1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.61-7.37 (m, 3H), 7.32 (s, 1H), 7.20(d, J=8.6, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 3.50 (m, 3H), 2.97 (m, 4H),2.77 (d, J=5.0, 4H), 2.59 (d, J=11.9, 2H), 2.26 (s, 3H), 2.12 (s, 3H),2.07 (m, 2H), 1.48 (m, 2H), 0.92 (d, J=8.0, 9H) ppm.

I-6:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 518.22 (M+H), 516.30 (M−H); ¹H NMR (300 MHz, DMSO) δ 9.20 (s,1H), 9.14 (m, 1H), 8.40 (s, 1H), 7.85 (s, 2H), 7.63 (s, 2H), 7.42-7.25(m, 1H), 7.14 (m, 1H), 7.06-6.81 (m, 1H), 3.51-3.04 (m, 4H), 2.67 (d,J=27.5, 4H), 2.08 (m, 6H), 1.41 (m, 2H), 0.91 (d, J=5.2, 9H) ppm.

I-7:N4-(3-n-propylbenzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.41 (s, NH), 8.50 (s, NH), 8.14 (s, 1H),8.09-7.86 (m, 2H), 7.64-7.23 (m, 6H), 3.68 (t, J=4.7, 2H), 3.07 (s, 3H),2.11 (s, 3H), 1.63 (tq, J=4.4, 9.8, 2H), 0.81 (t, J=7.6, 3H).

I-8:N4-(3-n-propylbenzo[d]oxazol-2(3H)-on-5-yl)-N2-((4-methylsulfonylamino)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.29 (s, NH), 8.99 (s, NH), 8.40 (s, NH), 7.86(s, 1H), 7.54 (d, J=12.1, 3H), 7.37 (d, J=8.4, 1H), 7.27 (d, J=7.2, 1H),7.06-6.87 (m, 2H), 3.72 (t, J=10.9, 2H), 2.84 (s, 3H), 2.08 (s, 3H),1.63 (tq, J=12.2, 17.8, 2H), 0.81 (t, J=9.4, 3H).

I-9:N4-(3-isopropylbenzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.39 (s, NH), 8.43 (s, NH), 8.13 (m, 2H),8.07-7.85 (m, 2H), 7.51 (m, 2H), 7.42-7.17 (m, 2H), 4.43-4.34 (m, 1H),3.05 (s, 3H), 2.11 (s, 3H), 1.39 (d, J=6.9, 6H).

I-10:N4-(3-isopropylbenzo[d]oxazol-2(3H)-on-5-yl)-N2-((4-methylsulfonylamino)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.27 (s, NH), 8.97 (s, NH), 8.35 (s, NH), 8.12(s, 1H), 7.86 (s, 1H), 7.52 (m, 3H), 7.25 (d, J=9.2, 1H), 6.95 (d,J=8.9, 2H), 4.50-4.31 (m, 1H), 2.84 (s, 3H), 2.09 (s, 3H), 1.40 (d,J=6.9, 6H).

I-11:N4-(benzimidazolin-2-on-5-yl)-N2-((3-aminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 411.95; ¹H NMR (300 MHz, DMSO) δ 10.72 (s, 1H), 10.68 (s,1H), 10.11 (br s, 1H), 9.53 (br s, 1H), 7.88 (br s, 2H), 7.75 (s, 1H),7.47 (s, 1H), 7.37 (br s, 2H), 7.28 (d, J=8.2, 1H), 7.13-7.08 (m, 2H),6.96 (d, J=8.2, 1H), 2.19 (s, 3H).

I-12:N4-(benzimidazolin-2-on-5-yl)-N2-((4-aminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 411.95; ¹H NMR (300 MHz, DMSO) δ 10.75 (s, 1H), 10.72 (s,1H), 10.40 (s, 1H), 9.63 (s, 1H), 7.89 (s, 1H), 7.57 (dd, J=8.9, 8.9,4H), 7.21 (br s, 1H), 7.03-6.89 (m, 4H), 2.15 (s, 3H).

I-13:5-(5-fluoro-2-(4-aminosulfonylphenylamino)pyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one

LCMS (M+) m/z 415.92; ¹H NMR (300 MHz, DMSO) δ 10.67 (s, 1H), 10.61 (s,1H), 9.64 (br d, J=6.8, 1H), 9.42 (br d, J=9.1, 1H), 8.14 (dd, J=2.3,3.8, 1H), 7.82 (br d, J=8.9, 2H), 7.61 (br d, J=8.9, 2H), 7.31 (br d,J=8.2, 1H), 7.17-7.15 (m, 3H), 6.94 (d, J=8.2, 1H).

I-14:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-aminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 430.42; ¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.34 (s,1H), 8.39 (s, 1H), 8.10 (s, 1H), 8.03 (br s, 1H), 7.94 (s, 1H), 7.45 (brd, J=8.6, 1H), 7.38 (d, J=1.7, 1H), 7.33-7.31 (m, 2H), 7.28-7.25 (m,3H), 2.16 (s, 3H).

I-15:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-aminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 412.93; ¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 10.00 (brs, 1H), 9.26 (br s, 1H), 7.96 (s, 1H), 7.71-7.61 (m, 4H), 7.34 (br s,2H), 7.34-7.24 (m, 3H), 2.19 (s, 3H).

I-16:N2-((3-methylsulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.50 (s, 1H), 9.40 (s, 1H), 8.39 (s, 1H), 8.17(s, 1H), 8.05 (d, J=7.5, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.38-7.32 (m,3H), 7.02 (d, J=8.4, 1H), 3.10 (s, 3H), 2.11 (s, 3H).

I-17:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 411.95; ¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.05 (brs, 1H), 9.20 (br s, 1H), 7.98 (s, 1H), 7.80 (d, J=9.0, 2H), 7.71 (d,J=9.0, 2H), 7.37 (d, J=9.0, 1H), 7.31-7.28 (m, 2H), 3.16 (s, 3H), 2.20(s, 3H).

I-18:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-aminosulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 416.89; ¹H NMR (300 MHz, DMSO) δ 11.63 (s, 1H), 9.58 (s,1H), 9.46 (s, 1H), 8.16 (d, J=3.7, 1H), 8.13 (s, 1H), 7.97 (br d, J=7.7,1H), 7.57 (dd, J=2.1, 8.7, 1H), 7.46-7.33 (m, 3H), 7.33-7.23 (m, 3H).

I-19:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-aminosulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 416.94; ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.69 (s,1H), 9.52 (s, 1H), 8.19 (d, J=3.7, 1H), 7.83 (d, J=8.9, 2H), 7.65 (d,J=8.9, 2H), 7.51 (br d, J=8.7, 1H), 7.38 (d, J=1.7, 1H), 7.30 (d, J=8.7,1H), 7.16 (br s, 2H).

I-20:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 416.37; ¹H NMR (300 MHz, DMSO) δ 11.68 (br s, 1H), 9.66(s, 1H), 9.45 (s, 1H), 8.23 (s, 1H), 8.18 (d, J=3.7, 1H), 8.08 (d,J=9.1, 1H), 7.54-7.37 (m, 4H), 7.24 (d, J=8.6, 1H), 3.16 (s, 3H).

I-21:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-methylsulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 415.92; ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.84 (s,1H), 9.56 (s, 1H), 8.21 (d, J=3.4, 1H), 7.92 (d, J=8.9, 2H), 7.73 (d,J=8.9, 2H), 7.47 (br d, J=8.6, 1H), 7.41 (br s, 1H), 7.33 (d, J=8.6,1H), 3.16 (s, 3H).

I-22:N4-(benzimidazolin-2-on-5-yl)-N2-(3-methylsulfonyl)phenyl-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 411.04; ¹H NMR (300 MHz, DMSO) δ 10.71 (s, 1H), 10.67 (s,1H), 10.18 (br s, 1H), 9.46 (br s, 1H), 8.02-7.82 (m, 3H), 7.57 (d,J=7.0, 1H), 7.39 (dd, J=8.0, 8.0, 1H), 7.17-7.02 (m, 2H), 6.96 (d,J=8.0, 1H), 3.14 (s, 3H), 2.19 (s, 3H).

I-23:N4-(benzimidazolin-2-on-5-yl)-N2-(4-methylsulfonyl)phenyl-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 414.94; ¹H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.63 (s,1H), 9.79 (s, 1H), 9.49 (s, 1H), 8.15 (d, J=3.8, 1H), 7.89 (d, J=8.5,2H), 7.68 (d, J=8.5, 2H), 7.27 (d, J=8.2, 1H), 7.19 (s, 1H), 6.96 (d,J=8.2, 1H), 3.14 (s, 3H).

I-24:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-aminosulfonyl-4-methyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 427.02; ¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 10.05 (brs, 1H), 9.42 (br s, 1H), 7.89 (s, 1H), 7.84 (br s, 1H), 7.74 (br d,J=6.8, 1H), 7.36-3.26 (m, 5H), 7.20 (d, J=8.2, 1H), 3.49 (s, 3H,overlapped with H₂O), 2.19 (s, 3H).

I-25:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-tert-butylaminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 469.05; ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.03 (brs, 1H), 9.35 (br s, 1H), 7.93 (s, 1H), 7.89-7.85 (m, 2H), 7.58-7.19 (m,6H), 2.20 (s, 3H), 1.12 (s, 9H).

I-26:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-cyanophenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 359.06; ¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 10.07 (brs, 1H), 9.34 (br s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.69-7.66 (m, 1H),7.51-7.38 (m, 2H), 7.33 (d, J=8.3, 1H), 7.28-7.16 (m, 2H), 2.19 (s, 3H).

I-27:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-cyanophenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 359.47; ¹H NMR (300 MHz, DMSO) δ 11.09 (br s, 1H), 9.64(s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.88 (d, J=8.8, 2H),7.58 (d, J=8.8, 2H), 7.38 (s, 1H), 7.32 (s, 1H), 2.16 (s, 3H).

I-28:N4-(benzimidazolin-2-on-5-yl)-N2-(3-cyanophenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 358.02; ¹H NMR (300 MHz, DMSO) δ 10.67 (s, 2H), 10.43 (s,1H), 9.55 (s, 1H), 7.97 (d, J=11.6, 2H), 7.71 (d, J=8.1, 1H), 7.47-7.36(m, 2H), 7.18-6.92 (m, 3H), 2.19 (s, 3H).

I-29:N4-(benzimidazolin-2-on-5-yl)-N2-(4-cyanophenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 358.50; ¹H NMR (300 MHz, DMSO) δ 10.75 (s, 1H), 10.68 (s,1H), 10.08 (br s, 1H), 9.24 (br s, 1H), 7.93 (s, 1H), 7.73 (d, J=8.7,2H), 7.55 (d, J=8.7, 2H), 7.10-7.08 (m, 2H), 7.00 (d, J=8.7, 1H), 2.18(s, 3H).

I-30:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-(morpholinosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 482.98; ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.05 (brs, 1H), 9.26 (br s, 1H), 8.02 (d, J=8.0, 1H), 7.96 (s, 1H), 7.81 (s,1H), 7.47 (dd, J=8.0, 8.0, 2H), 7.41-7.23 (m, 3H), 3.64-3.62 (m, 4H),2.85-2.83 (m, 4H), 2.19 (s, 3H).

I-31:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-(morpholinosulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 486.93; ¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 9.68 (s,1H), 9.54 (s, 1H), 8.19 (d, J=3.7, 1H), 8.14 (d, J=9.2, 1H), 8.03 (br s,1H), 7.49 (dd, J=8.0, 8.0, 2H), 7.42 (s, 1H), 7.26 (dd, J=9.2, 9.2, 2H),3.66-3.64 (m, 4H), 2.88-2.86 (m, 4H).

I-32:N4-(benzimidazolin-2-on-5-yl)-N2-(3-(morpholinosulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 486.04; ¹H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.58 (s,1H), 9.63 (s, 1H), 9.45 (s, 1H), 8.17-8.14 (m, 2H), 7.97 (s, 1H), 7.44(dd, J=7.8, 8.0, 1H), 7.31 (d, J=8.2, 1H), 7.24 (d, J=7.8, 1H), 7.20 (s,1H), 6.92 (d, J=8.2, 1H), 3.66-3.64 (m, 4H), 2.88-2.86 (m, 4H).

I-33:N4-(3-phosphorylmethylbenzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 522.40; ¹H NMR (300 MHz, D₂O) δ 7.68 (br s, 2H), 7.59 (brd, J=6.7, 1H), 7.40-7.21 (m, 4H), 7.06 (d, J=8.5, 1H), 5.38 (d, J=5.7,2H), 3.06 (s, 3H), 2.01 (s, 3H).

I-34:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((3-aminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 440.03; ¹H NMR (300 MHz, DMSO) δ 10.15 (br s, 1H), 9.51(br s, 1H), 7.92 (s, 1H), 7.87 (d, J=8.3, 1H), 7.78 (s, 1H), 7.47 (d,J=7.9, 1H), 7.38-7.36 (m, 2H), 7.28-7.23 (m, 2H), 7.20 (d, J=8.3, 1H),3.40 (s, 3H), 3.27 (s, 3H), 2.21 (s, 3H).

I-35:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((4-aminosulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 440.03; ¹H NMR (300 MHz, DMSO) δ 10.20 (br s, 1H), 9.54(br s, 1H), 7.95 (s, 1H), 7.65 (d, J=8.8, 2H), 7.57 (d, J=8.8, 2H), 7.40(s, 1H), 7.26-7.20 (m, 3H), 3.41 (s, 3H), 3.31 (s, 3H), 2.21 (s, 3H).

I-36:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 439.01; ¹H NMR (300 MHz, DMSO) δ 10.37 (br s, 1H), 9.62(br s, 1H), 7.95-7.90 (m, 3H), 7.56 (d, J=7.6, 1H), 7.34-7.39 (m, 2H),7.25-7.18 (m, 2H), 3.40 (s, 3H), 3.26 (s, 3H), 3.09 (s, 3H), 2.21 (s,3H).

I-37:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((3-methylsulfonylamino)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 454.00; ¹H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.89 (s,1H), 9.82 (s, 1H), 7.88 (s, 1H), 7.36 (s, 1H), 7.32 (d, J=8.1, 1H), 7.20(br s, 2H), 7.12 (br s, 1H), 7.07 (dd, J=8.1, 8.1, 1H), 6.94 (br d,J=7.8, 1H), 3.40 (s, 3H), 3.27 (s, 3H), 2.97 (s, 3H), 2.22 (s, 3H).

I-38:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((4-methylsulfonylamino)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 454.02; ¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 9.89 (s,1H), 9.72 (s, 1H), 7.87 (s, 1H), 7.38-7.35 (m, 3H), 7.20 (s, 2H), 7.03(d, J=8.7, 2H), 3.41 (s, 3H), 3.31 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H).

I-39:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((3-aminosulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 443.99; ¹H NMR (300 MHz, DMSO) δ 9.52 (s, 1H), 9.41 (s,1H), 8.13 (d, J=3.6, 1H), 8.10 (s, 1H), 8.03-7.99 (m, 1H), 7.62 (br s,1H), 7.42-7.34 (m, 3H), 7.29 (br s, 2H), 7.14 (br d, J=8.4, 1H), 3.37(s, 3H, overlapped with H₂O), 3.33 (s, 3H).

I-40:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((4-aminosulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 443.99; ¹H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.47 (s,1H), 8.16 (d, J=3.6, 1H), 7.83 (d, J=8.7, 2H), 7.62-7.59 (m, 3H), 7.34(d, J=8.7, 1H), 7.17-7.15 (m, 3H), 3.38 (s, 3H, overlapped with H₂O),3.32 (s, 3H).

I-41:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 442.95; ¹H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 9.44 (s,1H), 8.20 (s, 1H), 8.16 (d, J=3.7, 1H), 8.09 (br d, J=6.0, 1H), 7.57 (s,1H), 7.46-7.42 (m, 2H), 7.38 (br d, J=8.3, 1H), 7.14 (d, J=8.3, 1H),3.38 (s, 3H), 3.32 (s, 3H), 3.13 (s, 3H).

I-42:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((3-methylsulfonylamino)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 457.96; ¹H NMR (300 MHz, DMSO) δ 9.59 (br s, 1H), 9.34 (s,1H), 9.25 (s, 1H), 8.09 (d, J=3.7, 1H), 7.61 (s, 1H), 7.56 (d, J=8.4,1H), 7.45 (s, 1H), 7.40 (d, J=8.4, 1H), 7.15-7.08 (m, 2H), 6.75 (d,J=8.0, 1H), 3.37 (s, 3H, partially overlapped with H₂O), 3.31 (s, 3H),2.98 (s, 3H).

I-43:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-((4-methylsulfonylamino)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 458.02; ¹H NMR (300 MHz, DMSO) δ 9.38 (s, 1H), 9.34 (s,1H), 9.20 (s, 1H), 8.08 (d, J=3.8, 1H), 7.63 (s, 1H), 7.60-7.58 (m, 2H),7.31 (br d, J=8.3, 1H), 7.13 (d, J=8.3, 1H), 7.02 (d, J=8.8, 2H), 3.38(s, 3H, partially overlapped with H₂O), 3.31 (s, 3H), 2.91 (s, 3H).

I-44:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-cyanophenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 362.96; ¹H NMR (300 MHz, DMSO) δ 9.72 (s, 1H), 9.70 (br s,1H), 9.51 (s, 1H), 8.27 (s, 1H), 8.19 (d, J=3.8, 1H), 7.81 (d, J=9.4,1H), 7.47-7.21 (m, 5H).

I-45:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-cyanophenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 362.95; ¹H NMR (300 MHz, DMSO) δ 11.84 (br s, 1H), 9.86(s, 1H), 9.55 (s, 1H), 8.20 (d, J=3.7, 1H), 7.88 (d, J=8.8, 2H), 7.65(d, J=8.8, 2H), 7.44-7.41 (m, 2H), 7.31 (d, J=8.4, 1H).

I-46:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 419.10; ¹H NMR (300 MHz, DMSO) δ 11.62 (br s, 1H), 8.87(s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.38-7.34 (m, 2H),7.24 (d, J=8.2, 1H), 7.16 (d, J=8.2, 1H), 7.01 (dd, J=8.2, 8.2, 1H),6.47 (d, J=8.2, 1H), 3.65-3.62 (m, 4H), 2.91-2.88 (m, 4H), 2.13 (s, 3H).

I-47:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-morpholinyl)phenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 423.07; ¹H NMR (300 MHz, DMSO) δ 11.92 (br s, 1H), 9.39(s, 1H), 9.12 (s, 1H), 8.12 (d, J=3.7, 1H), 7.47-7.45 (m, 2H), 7.29-7.23(m, 2H), 7.18 (d, J=8.1, 1H), 7.06 (dd, J=8.1, 8.1, 1H), 6.52 (d, J=8.2,1H), 3.68-3.65 (m, 4H), 2.97-2.94 (m, 4H).

I-48:N4-(benzo[d]oxazol-2(3H)-on-6-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.90(s, 1H), 7.81 (s, 1H), 7.37 (d, J=8.3, 1H), 7.27 (s, 1H), 7.14 (d,J=8.3, 1H), 7.07-7.01 (m, 2H), 6.58-6.50 (m, 1H), 3.68-3.65 (m, 4H),2.95-2.92 (m, 4H), 2.14 (s, 3H); LCMS (M+) m/z 419.03.

I-49:N4-(3-methylbenzo[d]oxazol-2(3H)-on-6-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.00 (br s, 1H), 8.50 (br s, 1H), 8.90 (s, 1H),7.88 (s, 1H), 7.44 (d, J=8.2, 1H), 7.25-7.22 (m, 2H), 7.15 (d, J=8.2,1H), 7.05 (dd, J=8.2, 8.2, 1H), 6.58-6.51 (m, 1H), 3.67-3.64 (m, 4H),3.39 (s, 3H), 2.93-2.90 (m, 4H), 2.15 (s, 3H); LCMS (M+) m/z 433.11.

I-50:N2-(4-(methylsulfonylamino)phenyl)-N4-(1H-benzo[d]imidazol-2(3H)-on-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.52 (s, 1H), 10.48 (s, 1H), 9.23 (s, 1H),8.87 (s, 1H), 8.19 (s, 1H), 7.79 (s, 1H), 7.57 (d, J=8.8, 2H), 7.14 (d,J=8.2, 1H), 7.09 (s, 1H), 6.93 (d, J=8.8, 2H), 6.85 (d, J=8.2, 1H), 2.85(s, 3H), 2.06 (s, 3H).

I-51:N2-(4-(methylsulfonylamino)phenyl)-N4-(1H-benzo[d]imidazol-2(3H)-on-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.52 (d, J=9.6, 2H), 9.29 (s, 1H), 9.17 (s,1H), 9.08 (s, 1H), 8.00 (s, 1H), 7.57 (d, J=7.8, 2H), 7.25 (d, J=8.3,1H), 7.14 (s, 1H), 6.99 (d, J=7.8, 2H), 6.84 (d, J=8.3, 1H), 2.86 (s,3H).

I-52:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-methylsulfonylamino)phenyl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 9.29 (s, 1H), 9.03 (s, 1H), 8.43(s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.55 (d, J=8.6, 2H), 7.30 (d,J=8.6, 2H), 7.20 (d, J=8.2, 1H), 6.97 (d, J=8.2, 2H), 2.86 (s, 3H), 2.08(s, 3H).

I-53:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-methylsulfonylamino)phenyl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.57 (br s, 1H), 9.34-9.30 (m, 2H), 9.18 (s,1H), 8.05 (d, J=3.5, 1H), 7.56 (d, J=8.6, 2H), 7.44 (d, J=8.6, 1H), 7.35(s, 1H), 7.20 (d, J=8.6, 1H), 7.02 (d, J=8.6, 2H), 2.87 (s, 3H).

I-54:N2-(3-(methylsulfonylamino)phenyl)-N4-(1H-benzo[d]imidazol-2(3H)-on-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.53 (s, 1H), 10.46 (s, 1H), 9.50 (s, 1H),8.89 (s, 1H), 8.15 (d, J=7.6, 1H), 7.79 (s, 1H), 7.59 (d, J=8.2, 1H),7.35 (s, 1H), 7.21 (d, J=10.1, 1H), 7.12 (s, 1H), 6.98 (dd, J=8.2, 1H),6.85 (d, J=8.2, 1H), 6.64 (d, J=6.9, 1H), 2.94 (s, 3H), 2.07 (s, 3H).

I-55:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonylamino)phenyl)-5-methylpyrimidine-2,4-diamineformate salt

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.53 (s, 1H), 9.04 (s, 1H), 8.34(s, 1H), 7.85 (s, 1H), 7.56 (d, J=8.7, 1H), 7.40 (d, J=6.2, 1H), 7.39(s, 1H), 7.34 (s, 1H), 7.20 (d, J=8.6, 1H), 7.05 (t, J=8.1, 1H), 6.67(d, J=8.3, 1H), 2.95 (s, 3H), 2.08 (d, J=8.8, 4H).

I-56:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonylamino)phenyl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.63 (br s, 1H), 9.57 (s, 1H), 9.33 (s, 1H),9.25 (s, 1H), 8.06 (d, J=3.6, 1H), 7.55-7.50 (m, 2H), 7.42-7.40 (m, 2H),7.21 (d, J=8.6, 1H), 7.11 (dd, J=8.1, 8.1, 1H), 6.71 (d, J=8.2, 1H),2.95 (s, 3H).

I-57:N2-((3-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 9.58 (s, 1H), 8.13 (d, J=3.8,1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=7.3, 1H), 7.50 (d, J=10.4,1H), 7.41-7.36 (m, J=7.5, 2H), 7.26 (s, 2H), 7.19 (d, J=8.5, 1H), 3.33(s, 3H).

I-58:N2-(4-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.51 (s, 1H), 8.14 (d, J=3.6,1H), 7.97 (s, 1H), 7.81 (d, J=8.8, 2H), 7.62 (d, J=8.8, 2H), 7.49 (d,J=8.4, 1H), 7.20 (d, J=8.4, 1H), 7.11 (s, 2H), 3.35 (s, 3H).

I-59:N2-((3-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 9.53 (s, 1H), 8.19 (s, 1H), 8.15(d, J=3.7, 1H), 8.02 (d, J=8.8, 1H), 7.99 (s, 1H), 7.54-7.36 (m, 3H),7.19 (d, J=8.5, 1H), 3.34 (s, 3H), 3.12 (s, 3H).

I-60:N2-(4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.79 (s, 1H), 9.56 (s, 1H), 8.16 (d, J=3.7,1H), 7.97 (s, 1H), 7.88 (d, J=8.9, 2H), 7.70 (d, J=8.8, 2H), 7.45 (s,1H), 7.22 (d, J=8.5, 1H), 3.34 (s, 3H), 3.12 (s, 3H).

I-61:N2-((3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.61 (s, 1H), 9.58 (s, 1H), 9.43 (s, 1H), 8.09(d, J=3.9, 1H), 7.99 (s, 1H), 7.50 (t, J=9.9, 2H), 7.40 (s, 1H), 7.16(dd, J=8.2, 15.3, 2H), 6.76 (d, J=5.6, 1H), 3.33 (s, 3H), 2.96 (s, 3H).

I-62:N2-((4-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.70 (s, 1H), 9.44 (s, 2H), 8.10 (d, J=4.0,1H), 7.93 (s, 1H), 7.51 (d, J=8.8, 2H), 7.45 (d, J=8.5, 1H), 7.18 (d,J=8.5, 1H), 7.07 (d, J=8.8, 2H), 3.33 (s, 3H), 2.91 (s, 3H).

I-63:N2-((3-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 9.51 (s, 1H), 7.90 (s, 1H), 7.79(d, J=8.1, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.46 (d, J=7.9, 1H),7.39-7.28 (m, 4H), 7.22 (d, J=8.4, 1H), 3.35 (s, 3H), 2.15 (s, 3H).

I-64:N2-((4-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.22 (s, 1H), 9.45 (s, 1H), 7.92 (s, 1H), 7.65(s, 1H), 7.60 (s, 4H), 7.37 (dd, J=1.9, 8.4, 1H), 7.26 (d, J=8.4, 1H),7.20 (s, 2H), 3.37 (s, 3H), 2.15 (s, 3H).

I-65:N2-((3-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.34 (s, 1H), 7.94-7.87 (m,J=10.1, 3H), 7.66 (s, 1H), 7.51 (d, J=7.8, 1H), 7.43 (t, J=7.8, 1H),7.34 (d, J=10.1, 1H), 7.22 (d, J=8.4, 1H), 3.35 (s, 3H), 3.09 (s, 3H),2.15 (s, 3H).

I-66:N2-((4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.35 (s, 1H), 7.95 (s, 1H),7.82-7.61 (m, 5H), 7.35 (d, J=8.3, 1H), 7.27 (d, J=8.3, 1H), 3.36 (s,3H), 3.13 (s, 3H), 2.16 (s, 3H).

I-67:N2-((3-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.42 (s, 1H), 7.92 (s, 1H), 7.77(d, J=9.3, 2H), 7.43 (d, J=6.6, 2H), 7.35-7.23 (m, 5H), 3.21 (s, 3H),2.16 (s, 3H).

I-68:N2-((4-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.33 (s, 1H), 7.94 (s, 1H), 7.65(d, J=8.9, 2H), 7.57 (d, J=8.9, 2H), 7.48 (s, 1H), 7.36 (d, J=8.6, 1H),7.29 (d, J=8.6, 1H), 7.20 (s, 2H), 3.26 (s, 3H), 2.16 (s, 3H).

I-69:N2-((3-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 9.44 (s, 1H), 7.94 (s, 1H), 7.92(s, 1H), 7.84 (d, J=8.2, 1H), 7.51 (d, J=7.7, 1H), 7.44-7.39 (m, 2H),7.32 (d, J=8.6, 1H), 7.23 (d, J=8.6, 1H), 3.20 (s, 3H), 3.06 (s, 3H),2.16 (s, 3H).

I-70:N2-((4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.30 (s, 1H), 7.96 (s, 1H), 7.74(d, J=8.9, 2H), 7.65 (d, J=8.9, 2H), 7.48 (s, 1H), 7.38 (d, J=8.6, 1H),7.28 (d, J=8.6, 1H), 3.25 (s, 3H), 3.12 (s, 3H), 2.16 (s, 3H).

I-71:N2-((3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.73 (s, 1H), 9.57 (s, 1H), 7.87(s, 1H), 7.46 (s, 1H), 7.34-7.25 (m, 3H), 7.16 (s, 1H), 7.10 (t, J=8.0,1H), 6.86 (d, J=9.0, 1H), 3.22 (s, 3H), 2.93 (s, 3H), 2.16 (s, 3H).

I-72:N2-((4-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.63 (s, 2H), 7.85 (s, 1H), 7.46(s, 1H), 7.39-7.30 (m, 3H), 7.21 (d, J=8.6, 1H), 7.02 (d, J=8.6, 2H),3.26 (s, 3H), 2.90 (s, 3H), 2.15 (s, 3H).

I-73:N2-((3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.05 (s, 1H), 9.74 (s, 1H), 9.56 (s, 1H), 7.83(s, 1H), 7.65 (s, 1H), 7.36 (d, J=8.0, 1H), 7.29 (d, J=8.2, 1H), 7.23(d, J=8.2, 1H), 7.14 (dd, J=8.0, 2H), 6.89 (d, J=8.2, 1H), 3.35 (s, 3H),2.95 (s, 3H), 2.15 (s, 3H).

I-74:N2-((4-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.97 (s, 1H), 9.64 (s, 1H), 9.57 (s, 1H), 7.82(s, 1H), 7.65 (s, 1H), 7.33 (d, J=8.5, 3H), 7.22 (d, J=8.5, 1H), 7.05(d, J=8.5, 2H), 3.36 (s, 3H), 2.92 (s, 3H), 2.14 (s, 3H).

I-75:N2-((3-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.60 (d, J=4.2, 2H), 8.14 (d, J=4.2, 1H), 8.05(s, 1H), 7.89 (d, J=7.0, 1H), 7.68 (s, 1H), 7.42-7.24 (m, 6H), 3.27 (s,3H).

I-76:N2-((4-aminosulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.55 (s, 1H), 8.16 (d, J=3.6,1H), 7.77 (d, J=8.7, 2H), 7.67 (s, 1H), 7.60 (d, J=8.7, 2H), 7.38 (d,J=8.7, 1H), 7.30 (d, J=8.7, 1H), 7.13 (s, 2H), 3.28 (s, 3H).

I-77:N2-((3-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 9.56 (s, 1H), 8.16 (s, 2H), 7.99(d, J=8.9, 1H), 7.65 (s, 1H), 7.51-7.33 (m, 3H), 7.28 (d, J=8.8, 1H),3.27 (s, 3H), 3.09 (s, 3H).

I-78:N2-((4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.80 (s, 1H), 9.59 (s, 1H), 8.18 (d, J=3.6,1H), 7.86 (d, J=8.8, 2H), 7.70 (s, 1H), 7.66 (d, J=6.3, 2H), 7.39-7.30(m, 2H), 3.28 (s, 3H), 3.11 (s, 3H).

I-79:N2-((3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.70 (s, 1H), 9.62 (s, 1H), 9.48 (s, 1H), 8.12(d, J=4.0, 1H), 7.68 (s, 1H), 7.45-7.37 (m, 3H), 7.27 (d, J=8.6, 1H),7.13 (t, J=8.0, 1H), 6.77 (d, J=8.0, 1H), 3.26 (s, 3H), 2.94 (s, 3H).

I-80:N2-((4-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.72 (s, 1H), 9.43 (s, 2H), 8.12 (s, 1H), 7.65(s, 1H), 7.52 (d, J=8.7, 2H), 7.33 (d, J=8.7, 1H), 7.27 (d, J=8.7, 1H),7.04 (d, J=8.7, 2H), 3.26 (s, 3H), 2.88 (s, 3H).

I-81:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.49 (s, 1H), 8.96 (s, 1H), 8.91 (s, 1H), 8.31(s, 1H), 7.84 (s, 2H), 7.60 (d, J=8.3, 1H), 7.47 (s, 1H), 7.37 (d,J=8.6, 1H), 7.00 (dd, J=8.3, 12.6, 2H), 2.95 (s, 3H), 2.19 (s, 3H), 2.09(s, 3H).

I-82:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.93 (s, 1H), 9.50 (s, 1H), 9.07 (s, 1H), 7.83(s, 1H), 7.45 (s, 1H), 7.37-7.20 (m, 4H), 7.04 (d, J=8.3, 1H), 3.19 (s,3H), 2.87 (s, 3H), 2.23 (s, 3H), 2.15 (s, 3H).

I-83:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.53 (s, 1H), 9.04 (s, 1H), 7.81(s, 1H), 7.63 (s, 1H), 7.37-7.29 (m, 2H), 7.23 (d, J=7.6, 2H), 7.08 (d,J=8.3, 1H), 3.35 (s, 3H), 2.90 (s, 3H), 2.25 (s, 3H), 2.14 (s, 3H).

I-84:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 9.60 (s, 1H), 9.37 (s, 1H), 8.97(s, 1H), 8.10 (d, J=4.0, 1H), 7.50 (dd, J=6.1, 14.8, 2H), 7.42 (s, 1H),7.34 (s, 1H), 7.24 (d, J=8.6, 1H), 7.05 (d, J=8.5, 1H), 2.93 (s, 3H),2.21 (s, 3H).

I-85:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.69 (s, 1H), 9.40 (s, 1H), 8.99 (s, 1H), 8.11(d, J=4.0, 1H), 7.66 (s, 1H), 7.54-7.33 (m, 3H), 7.29 (d, J=8.6, 1H),7.06 (d, J=8.6, 1H), 3.23 (s, 3H), 2.90 (s, 3H), 2.22 (s, 3H).

I-86:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.67 (s, 1H), 9.42 (s, 1H), 8.97 (s, 1H), 8.09(d, J=4.1, 1H), 7.94 (s, 1H), 7.51 (d, J=8.4, 2H), 7.44 (s, 1H), 7.20(d, J=8.4, 1H), 7.08 (d, J=8.4, 1H), 3.34 (s, 3H), 2.94 (s, 3H), 2.23(s, 3H).

I-87:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 10.00 (s, 1H), 9.65 (s, 1H),9.50 (s, 1H), 7.83 (s, 1H), 7.52-7.04 (m, 6H), 2.98 (s, 3H), 2.14 (s,3H).

I-88:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.93 (s, 1H), 9.62 (s, 1H), 9.45 (s, 1H), 7.85(s, 1H), 7.43-7.21 (m, 5H), 7.12 (dd, J=9.3, 1H), 3.23 (s, 3H), 2.95 (s,3H), 2.15 (s, 3H).

I-89:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.95 (s, 1H), 9.61 (s, 1H), 9.45 (s, 1H), 7.83(s, 1H), 7.61 (s, 1H), 7.45-7.31 (m, 3H), 7.23 (d, J=8.4, 1H), 7.13 (dd,J=9.6, 1H), 3.35 (s, 3H), 2.97 (s, 3H), 2.14 (s, 3H).

I-90:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.50 (s, 2H), 9.36 (s, 1H), 8.09(d, J=3.9, 1H), 7.63-7.52 (m, 2H), 7.47 (d, J=8.8, 1H), 7.35 (s, 1H),7.23 (d, J=8.8, 1H), 7.10 (dd, J=8.8, 1H), 2.98 (s, 3H).

I-91:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.61 (s, 1H), 9.51 (s, 1H), 9.40 (s, 1H), 8.11(d, J=3.9, 1H), 7.63 (s, 1H), 7.58-7.47 (m, 2H), 7.39 (d, J=8.6, 1H),7.28 (d, J=8.6, 1H), 7.12 (dd, J=9.3, 1H), 3.26 (s, 3H), 2.96 (s, 3H).

I-92:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 9.51 (s, 1H), 9.46 (s, 1H), 8.10(d, J=3.9, 1H), 7.90 (s, 1H), 7.58-7.46 (m, 3H), 7.21-7.09 (m, 2H), 3.34(s, 3H), 2.99 (s, 3H).

I-93:N2-((4-methylsulfonyl-N-methylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.99 (s, 1H), 9.49 (s, 1H), 7.86(s, 1H), 7.43 (d, J=8.6, 2H), 7.32-7.14 (m, 5H), 3.17 (s, 3H), 2.88 (s,3H), 2.14 (s, 3H).

I-94:N2-((4-methylsulfonyl-N-methylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.59 (s, 1H), 7.90 (s, 1H),7.46-7.43 (m, 3H), 7.36 (d, J=8.6, 1H), 7.28-7.19 (m, 3H), 3.25 (s, 3H),3.16 (s, 3H), 2.88 (s, 3H), 2.15 (s, 3H).

I-95:N2-((4-methylsulfonyl-N-methylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.56 (s, 1H), 7.87 (s, 1H), 7.65(s, 1H), 7.43 (d, J=8.6, 2H), 7.34 (d, J=8.1, 1H), 7.26-7.23 (m, 3H),3.34 (s, 3H), 3.18 (s, 3H), 2.89 (s, 3H), 2.15 (s, 3H).

I-96:N2-((4-methylsulfonyl-N-methylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 9.59 (s, 1H), 9.47 (s, 1H), 8.11(d, J=3.9, 1H), 7.60 (d, J=8.6, 2H), 7.43 (d, J=8.6, 1H), 7.34 (s, 1H),7.28-7.17 (m, 3H), 3.17 (s, 3H), 2.89 (s, 3H).

I-97:N2-((4-methylsulfonyl-N-methylamino)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.49 (s, 1H), 8.11 (d, J=3.9,1H), 7.95 (s, 1H), 7.60 (d, J=8.8, 2H), 7.46 (d, J=8.8, 1H), 7.25-7.18(m, 3H), 3.33 (s, 3H), 3.18 (s, 3H), 2.90 (s, 3H).

I-98:N2-((3-aminosulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.51 (s, 1H), 9.39 (s, 1H), 8.45 (s, 1H), 8.04(s 1H), 7.95 (s, 1H), 7.88-7.85 (m, 2H), 7.38-7.23 (m, 5H), 7.02 (d,J=8.3, 1H), 2.11 (s, 3H).

I-99:N2-((4-aminosulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.41 (s, 1H), 8.42 (s, 1H), 7.91(s, 1H), 7.83-7.70 (m, 3H), 7.55 (d, J=8.7, 2H), 7.35 (d, J=8.4, 1H),7.14-7.00 (m, 3H), 2.11 (s, 3H).

I-100:N2-((3-methylsulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine;I-101:N2-((4-methylsulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine;I-102:N2-((3-methylsulfonylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine;I-103:N2-((4-methylsulfonylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine;I-104:N2-((3-methylsulfonylamino-4-methyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine;I-105:N2-((4-fluoro-3-methylsulfonylamino)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.50 (s, 1H), 9.47 (s, 1H), 9.08 (s, 1H), 8.35(s, 1H), 7.85-8.83 (m, 2H), 7.68-7.64 (m, 1H), 7.58 (d, J=8.5, 1H), 7.36(d, J=8.5, 1H), 7.10-6.93 (m, 2H), 2.99 (s, 3H), 2.09 (s, 3H).

I-106:N4-(benzoxazolin-2-on-5-yl)-N2-(3-trifluoromethoxyphenyl)-5-methylpyrimidine-2,4-diaminetrifluoroacetate salt; I-107:N4-(benzoxazolin-2-on-5-yl)-N2-(3-trifluoromethoxyphenyl)-5-fluoropyrimidine-2,4-diaminetrifluoroacetate salt; I-108:N4-(benzoxazolin-2-on-5-yl)-N2-(4-trifluoromethoxyphenyl)-5-methylpyrimidine-2,4-diaminetrifluoroacetate salt; I-109:N4-(benzoxazolin-2-on-5-yl)-N2-(4-trifluoromethoxyphenyl)-5-fluoropyrimidine-2,4-diaminetrifluoroacetate salt; I-110:N4-(benzoxazolin-2-on-5-yl)-N2-[3-trifluoromethyl-4-(4-ethylpiperazin-1-yl)phenyl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 514 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.51 (s, 1H), 9.22(s, 1H), 8.38 (s, 1H), 7.94 (s, 1H), 7.87 (m, 2H), 7.33-7.18 (m, 4H),2.80 (s, 4H), 2.49 (br s, 6H), 2.09 (s, 3H), 1.04 (t, 3H, J=6.3 Hz).

I-111:N4-(benzoxazolin-2-on-5-yl)-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 458 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 8.67 (s, 1H), 8.27(s, 1H), 7.80 (s, 1H), 7.31 (m, 4H), 7.19 (d, 1H, J=9.3 Hz), 6.69 (d,1H, J=8.7 Hz), 3.94 (s, 1H), 3.80 (s, 1H), 3.30 (d, 1H, J=10.2 Hz), 3.21(d, 1H, J=8.7 Hz), 3.15 (s, 1H), 2.92 d, 1H, J=10.5 Hz), 2.57 (s, 3H),2.07 (s, 3H), 2.04 (d, 1H, J=9.6 Hz), 1.99 (d, 1H, J=10.8 Hz), 2.00 (s,3H), 1.88 (d, 1H, J=10.8 Hz).

I-112:N4-(benzoxazolin-2-on-5-yl)-N2-[4-N-(t-butyl)aminosulfonylphenyl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 469 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.80 (s, 1H), 10.59(s, 1H), 9.81 (s, 1H), 7.94 (s, 1H), 7.60 (d, 2H, J=9.0 Hz), 7.53 (d,2H, J=8.7 Hz), 7.40 (s, 1H), 7.32 (d, 1H, J=9.0 Hz), 7.19 (m, 2H), 2.16(s, 3H), 1.03 (s, 9H).

I-113:N4-(benzoxazolin-2-on-5-yl)-N2-[4-methyl-3-N-(t-butyl)aminosulfonylphenyl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 483 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.66 (s, 1H), 9.90(s, 1H), 9.20 (s, 1H), 7.86 (s, 2H), 7.75 (d, 1H, J=6.9 Hz), 7.42 (s,1H), 7.26 (m, 3H), 7.13 (d, 1H, J=8.7 Hz), 2.48 (s, 3H), 2.13 (s, 3H),1.07 (s, 9H).

I-114:N4-(benzoxazolin-2-on-5-yl)-N2-[3-N-(i-propyl)aminosulfonylphenyl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 455 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.72 (s, 1H), 10.42(s, 1H), 9.68 (s, 1H), 7.91 (s, 1H), 8.10 (d, 1H, J=7.8 Hz), 7.68 (s,1H), 7.58 (d, 1H, J=7.2 Hz), 7.44 (d, 1H, J=7.8 Hz), 7.36 (t, 1H, J=7.5Hz), 7.27 (m, 2H), 3.16 (m, 1H), 2.16 (s, 3H), 0.91 (d, 6H, J=6.3 Hz).

I-115:N4-(benzoxazolin-2-on-5-yl)-N2-(3,4,5-trimethoxyphenyl)-5-fluoropyrimidine-2,4-diamine

LCMS (m/z): 428 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.61 (s, 1H), 9.70(s, 1H), 9.38 (s, 1H), 8.11 (d, 1H, J=4.2 Hz), 7.44 (dd, 1H, J=1.8 and8.7 Hz), 7.34 (d, 1H, J=1.8 Hz), 7.19 (d, 1H, J=8.4 Hz), 6.93 (s, 2H),3.58 (s, 3H), 3.57 (s, 6H).

I-116:N2-(3-(difluoromethoxy)-4-methoxyphenyl)-N4-(benzo[d]oxazol-2(3H)-on-5-yl)-5-methylpyrimidine-2,4-diamine

LCMS: purity: 96.68%; MS (m/e): 430.24 (M+H); ¹H NMR (300 MHz, DMSO) δ11.33 (br, 1H), 8.92 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.55 (s, 1H),7.46 (d, J=8.7, 1H), 7.30 (d, J=8.7, 1H), 7.29 (s, 1H), 7.18 (d, J=9.0,1H), 6.92 (d, J=8.7, 1H), 6.81 (t, J=75, 1H), 3.73 (s, 3H), 2.08 (s,3H); ¹⁹F NMR (282 MHz, DMSO) δ −96.44 (d, J=73).

I-117:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-trifluoromethylsulfonyl)phenyl-5-methylpyrimidine-2,4-diamine

LCMS: purity: 91.03%; MS (m/e): 466.14 (M+H); ¹H NMR (300 MHz, DMSO) δ11.62 (s, 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.00 (d, J=9.0, 2H), 7.98(d, J=4.2, 1H), 7.78 (d, J=8.7, 2H), 7.28 (s, 3H), 2.13 (s, 3H); ¹⁹F NMR(282 MHz, DMSO) δ −94.87.

I-118:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-trifluoromethylsulfonyl)phenyl-5-methylpyrimidine-2,4-diamine

LCMS: purity: 100%; MS (m/e): 466.14 (M+H); ¹H NMR (300 MHz, DMSO) δ11.56 (s, 1H), 9.64 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.30 (d, J=7.2,1H), 7.94 (s, 1H), 7.56 (t, J=7.8, 1H), 7.51 (t, J=7.2, 1H), 7.30 (m,2H), 7.22 (d, J=9.0, 1H), 2.11 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−94.39.

I-119:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3,4,5-trimethoxy)phenyl-5-methylpyrimidine-2,4-diamine

LCMS: purity: 99.98%; MS (m/e): 424.28 (M+H); ¹H NMR (300 MHz, DMSO) δ11.56 (s, 1H), 9.07 (br, 1H), 8.59 (br, 1H), 7.84 (s, 1H), 7.31 (d,J=9.1, 2H), 7.18 (d, J=8.4, 1H), 6.95 (s, 2H), 3.56 (s, 3H), 3.52 (s,6H), 2.09 (s, 3H).

I-120:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-3-methyl)phenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 472.13 (M+H); ¹H NMR (CD₃OD, 300 MHz) 8.37 (m, 2H), 7.78-6.95(m, 7H), 3.59-3.42 (m, 9H), 2.42-2.21 (m, 4H), 2.13 (s, 3H), 2.11 (s,3H).

I-121:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)phenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 472.12 (M+H); ¹H NMR (CD₃OD, 300 MHz) 8.40 (m, 2H), 7.63-6.40(m, 9H), 3.95-3.53 (m, 4H), 2.81 (s, 3H), 2.66-2.15 (m, 7H), 2.13 (s,3H).

I-122N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-(dihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)-3-methyl)phenyl)-5-methylpyrimidine-2,4-diamine;

MS (ES) 486.17 (M+H); ¹H NMR (CD₃OD, 300 MHz) 8.35 (m, 2H), 7.71 (m,1H), 7.298-6.85 (m, 6H), 3.48 (m, 3H), 3.25-2.78 (m, 6H), 2.16 (s, 3H),2.09 (s, 3H), 2.03-1.51 (m, 6H).

I-123:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-(8-methyl-2,8-diazabicyclo[3.2.1]octan-2-yl)phenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 458.10 (M+H); ¹H NMR (CD₃OD, 300 MHz) 8.41 (brs, 2H), 7.68 (s,1H), 7.40-6.74 (m, 8H), 4.02 (brs, 2H), 3.59 (m, 2H), 3.17 (m, 2H), 2.87(s, 3H), 2.29-2.15 (m, 4H), 2.13 (s, 3H).

I-124:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-5-methyl-N2-[3-(morpholin-4-yl)-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.53 (s, 1H), 9.10 (s, 1H), 8.37 (s, 1H),7.88 (s, 1H), 7.47 (s, 1H), 7.32-7.18 (m, 3H), 7.00 (d, 1H, J=8.7 Hz),4.09 (q, 1H, J=5.4 Hz), 3.58 (s, 3H), 3.15 (d, 2H, J=5.1 Hz), 2.69 (s,3H), 2.08 (s, 3H); LCMS (m/z): 503 (M+H).

I-125:4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoicacid methyl ester

¹H NMR (DMSO, 300 MHz): δ 9.30 (s, 1H), 8.41 (s, 1H), 8.22-8.31 (m, 1H),8.17 (s, 1H), 7.91 (s, 1H), 7.67-7.78 (m, 2H), 7.54-7.65 (m, 1H),7.30-7.40 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 3.29-3.40 (m, 3H) 2.09 (s,3H) ppm; MS (ES) 392 (M+H).

I-126:4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoicacid

¹H NMR (DMSO, 300 MHz): δ 9.26 (s, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.41(br. s., 1H), 8.34 (d, J=8.3 Hz, 2H), 8.14 (s, 1H), 7.90 (s, 1H), 7.68(m, 2H), 7.44-7.52 (m, 1H), 7.27-7.38 (m, 1H), 2.04-2.15 (m, 3H) ppm; MS(ES) 378 (M+H).

I-127:N-(2-Diethylamino-ethyl)-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

MS (ES) 476 (M+H)

I-128:5-{2-[4-(3-Diethylamino-pyrrolidine-1-carbonyl)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

MS (ES) 502 (M+H)

I-129:5-[2-(4-Acetyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 9.31 (s, 1H), 8.38 (s, 1H), 8.20-8.33 (m, 1H), 8.18(s, 1H), 7.88 (s, 1H), 7.66-7.79 (m, 2H), 7.52-7.69 (m, 1H), 7.32-7.42(m, 2H), 7.25 (d, J=8.2 Hz, 1H), 2.23 (s, 3H) 2.09 (s, 3H) ppm; MS (ES)376 (M+H);

I-130:5-[2-(3-Acetyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.69 (s, 1H), 10.37 (br. s., 1H), 9.60 (br.s., 1H), 7.90 (d, J=7.4 Hz, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.7Hz, 1H), 7.29-7.43 (m, 1H), 7.14-7.27 (m, 4H), 2.39 (s, 3H), 2.14 (s,3H) ppm; MS (ES) 376 (M+H).

I-131:2-Methyl-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzonitrile

¹H NMR (DMSO, 300 MHz): δ 11.66 (s, 1H), 10.50 (br. s., 1H), 9.66 (br.s., 1H), 7.93 (d, J=3.6 Hz, 2H), 7.45 (dd, J=8.5, 1.7 Hz, 1H), 7.30 (d,J=8.3 Hz, 2H), 7.07-7.22 (m, 2H), 2.35 (s, 3H), 2.13 (s, 3H) ppm; MS(ES) 373 (M+H).

I-132:N,N-Dimethyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

MS (ES) 405 (M+H)

I-133:N-Methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.92 (s, 1H), 10.90 (s, 1H), 10.03 (s, 1H),8.52-8.28 (m, 1H), 7.95 (s, 1H), 7.67 (d, J=8.6, 2H), 7.45 (d, J=8.6,2H), 7.34 (s, 1H), 7.25 (s, 2H), 2.72 (s, 3H), 2.15 (s, 3H); ppm; MS(ES) 391 (M+H).

I-134:N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamideformate salt I-135:4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-N-phenyl-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.79 (s, 1H), 10.49-10.22 (m, 1H), 10.05 (s,1H), 9.71-9.38 (m, 1H), 7.95 (s, 1H), 7.79 (d, J=8.7, 1H), 7.73 (d,J=7.6, 1H), 7.62 (d, J=8.7, 1H), 7.39-7.22 (m, 5H), 7.12-7.02 (m, 1H),2.15 (s, 3H) ppm; MS (ES) 453 (M+H).

I-136:4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-2-pyrrolidin-1-yl-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.73 (s, 1H), 10.29 (s, 1H), 9.62 (s, 1H),7.97 (s, 1H), 7.73 (s, 1H), 7.49-7.11 (m, 2H), 7.00-6.52 (m, 2H),3.13-2.80 (m, 4H), 2.32-1.97 (m, 3H), 1.85-1.54 (m, 4H) ppm; MS (ES) 446(M+H).

I-137:N-Ethyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.64 (s, 1H), 9.32 (s, 1H), 8.47 (s, 1H),8.18 (s, 1H), 7.89 (d, J=9.8, 1H), 7.70 (d, J=8.8, 2H), 7.61 (d, J=8.8,2H), 7.45-7.15 (m, 3H), 3.30-3.18 (m, 2H), 2.10 (s, 3H), 1.08 (t, J=7.2,2H) ppm; MS (ES) 405 (M+H).

I-138:N-Cyclobutyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamideformic acid salt

MS (ES) 431 (M+H)

I-139:N-Isopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.64 (s, 1H), 9.31 (s, 1H), 8.47 (s, 1H),7.91 (s, 2H), 7.66 (dd, J=8.8, 22.3, 4H), 7.33 (s, 1H), 7.29-7.21 (m,2H), 4.18-3.93 (m, 1H), 2.10 (s, 3H), 1.12 (d, J=6.6, 6H) ppm; MS (ES)419 (M+H).

I-140:N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamideformate salt I-141:2-Chloro-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamidetrifluoroacetic acid salt

¹H NMR (DMSO, 300 MHz): δ 11.89-11.38 (m, 1H), 10.43-10.06 (m, 1H),9.77-9.20 (m, 1H), 7.93 (s, 1H), 7.67 (s, 1H), 7.58-7.36 (m, 1H), 7.29(m, 2H), 7.20 (m, 2H), 2.13 (s, 3H) ppm; MS (ES) 410/412 (M+H).

I-142:N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamidetrifluoroacetic acid salt I-143:N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.62 (s, 1H), 9.27 (s, 1H), 8.41 (s, 1H),8.14 (s, 1H), 7.90 (s, 1H), 7.65 (m, 3H), 7.29 (m, 3H), 3.33 (s, 3H),2.87-2.61 (m, 1H), 0.59 (m, 4H) ppm; MS (ES) 417 (M+H).

I-144:N-Cyclobutyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide;I-145:4-[5-Methyl-4-(2-oxo-3-propionyl-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

MS (ES) 433 (M+H)

I-146: di-tert-butyl(5-(2-(4-carbamoylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methylphosphate

¹H NMR (DMSO, 300 MHz): δ 9.38 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 7.95(s, 1H), 7.76 (dd, J=8.7, 26.3, 5H), 7.36 (s, 2H), 7.12 (s, 1H), 5.63(d, J=11.1, 2H), 2.12 (s, 3H), 1.31 (s, 18H) ppm; MS (ES) 599 (M+H).

I-147:(5-(2-(4-carbamoylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyldihydrogen phosphate

MS (ES) 487 (M+H)

I-148: sodium(5-(2-(4-carbamoylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methylphosphate

MS (ES) 487 (M+H)

I-150:(5-(2-(4-(cyclobutylcarbamoyl)phenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyldihydrogen phosphate

MS (ES) 541 (M+H)

I-151: sodium(5-(2-(4-(cyclobutylcarbamoyl)phenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzooxazol-3(2H)-yl)methyl phosphate

MS (ES) 541 (M+H)

I-152: di-tert-butyl(5-(2-(4-(cyclobutylcarbamoyl)phenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzooxazol-3(2H)-yl)methyl phosphate

MS (ES) 653 (M+H).

I-153:5-[2-(4-Chloro-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (300 MHz, DMSO) δ 9.49 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 8.14(s, 1H), 7.92 (s, 2H), 7.42 (d, J=8.8, 1H), 7.26 (m, 2H), 2.09 (s, 3H)ppm; MS (ES) 435/437 (M+H);

I-154:5-[5-Methyl-2-(4-methyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.71 (s, 1H), 10.59 (br. s., 1H), 9.68 (br. s.,1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.25 (d, J=8.5Hz, 2H), 7.08-7.20 (m, 2H), 2.32 (br. s., 3H), 2.13 (s, 3H) ppm; MS (ES)416 (M+H);

I-155:5-[5-Methyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.35 (s, 1H), 8.42 (s, 1H), 8.05 (s, 1H), 7.90(s, 2H), 7.32 (s, 2H), 7.23 (d, J=6.6, 2H), 2.43 (s, 3H), 2.08 (s, 3H)ppm; MS (ES) 448 (M+H).

I-156:4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-2-(4-methyl-piperidin-1-yl)-benzamide

MS (ES) 474 (M+H)

I-157:5-[2-(3-Cyclopentanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.39 (s, 1H), 8.40 (s, 1H), 8.15 (m, 2H), 7.91(s, 1H), 7.29 (m, 3H), 2.81 (m, 1H), 2.09 (s, 3H), 1.92-1.64 (m, 4H),1.68-1.38 (m, 4H) ppm; MS (ES) 466 (M+H).

I-158:5-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.38 (s, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 8.07(s, 1H), 7.88 (d, J=16.6, 2H), 7.41-7.16 (m, 3H), 7.11 (s, 1H), 2.09 (s,3H) ppm; MS (ES) 402 (M+H).

I-159:2-Methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoicacid methyl ester

MS (ES) 406 (M+H)

I-160:5-[5-Methyl-2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.75 (s, 1H), 10.16 (br. s., 1H), 9.23-9.61 (m,1H), 7.93 (s, 1H), 7.61-7.78 (m, 2H), 7.44-7.63 (m, 3H), 7.16-7.40 (m,2H), 2.13 (s, 3H) ppm; MS (ES) 402 (M+H);

I-161:5-[5-Methyl-2-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 486 (M+H)

I-162:5-[2-(3-Fluoro-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-onetrifluoroacetate salt

¹H NMR (DMSO, 300 MHz): δ 11.65 (s, 1H), 10.32-10.20 (m, 1H), 9.40-9.28(m, 1H), 7.95 (s, 1H), 7.81-7.66 (d, 1H), 7.57 (s, 1H), 7.33-7.06 (m,4H), 2.13 (s, 3H) ppm; MS (ES) 420 (M+H).

I-163:5-[2-(4-Fluoro-3-trifluoromethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 436 (M+H).

I-164:5-[5-Methyl-2-(4-methyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-onetrifluoracetic acid salt

For ¹H NMR see 1-154; MS (ES) 413 (M+H).

I-165:5-{2-[4-(2-Methoxy-ethoxy)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.67-11.58 (m, 1H), 9.65-9.56 (m, 1H),9.06-8.94 (m, 1H), 7.86 (m, 2H), 7.23 (d, J=8.0, 1H), 7.19-7.05 (m, 1H),6.97 (d, J=8.7, 2H), 6.83 (m, 1H), 4.10-3.99 (m, 2H), 3.60 (m, 2H), 3.28(s, 3H), 2.10 (s, 3H) ppm; MS (ES) 476 (M+H).

I-166:5-[2-(4-Isopropyl-3-methyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 390 (M+H)

I-167:5-[2-(3-Chloro-4-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.79 (s, 1H), 10.96 (br. s., 1H), 9.73 (br. s.,1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.28-7.45 (m,2H), 7.10-7.26 (m, 2H), 2.14 (s, 3H) ppm; MS (ES) 436 (M+H);

I-168:5-[2-(4-Ethoxy-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 446 (M+H)

I-169:5-[2-(3,5-Bis-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 470 (M+H)

I-170:2-Methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoicacid

MS (ES) 392 (M+H)

I-171:N-Ethyl-2-methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

MS (ES) 419 (M+H)

I-172:5-[2-(4-Chloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.16 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.87(s, 1H), 7.67 (d, J=8.9, 1H), 7.43-7.20 (m, 2H), 7.14 (d, J=8.9, 1H),2.08 (s, 3H) ppm; MS (ES) 368 (M+H).

I-173:5-[2-(3-Chloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 368 (M+H)

I-174:5-(5-Methyl-2-phenylamino-pyrimidin-4-ylamino)-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.93 (s, 1H), 10.81 (s, 1H), 9.85 (s, 1H), 7.90 (s,1H), 7.40 (d, J=8.0 Hz, 2H), 7.26-7.32 (m, 2H), 7.11-7.23 (m, 3H),6.98-7.08 (m, 1H), 2.13 (s, 3H) ppm; MS (ES) 334 (M+H);

I-175:5-[2-(3-Bromo-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 412/414 (M+H)

I-176:5-[2-(4-Chloro-2,5-dimethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 396/398 (M+H)

I-177:N-{4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-2-trifluoromethyl-phenyl}-acetamide

MS (ES) 459 (M+H)

I-178:5-[2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.78 (s, 1H), 10.11 (br. s., 1H), 9.65 (br. s.,1H), 7.84 (s, 1H), 7.26-7.36 (m, 1H), 7.15-7.24 (m, 3H), 6.90-7.13 (m,2H), 2.12 (m, 6H), 1.97 (s, 3H) ppm; MS (ES) 362 (M+H);

I-179:5-[2-(4-Cyclohexylmethoxy-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.72 (s, 1H), 10.32 (s, 1H), 9.77 (s, 1H),7.86 (s, 1H), 7.56 (s, 2H), 7.32-7.02 (m, 3H), 2.48 (m, 2H), 2.13 (s,3H), 1.73 (s, 5H), 1.37-0.90 (m, 6H) ppm; MS (ES) 514 (M+H).

I-180:5-[2-(4-Chloro-3-trifluoromethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 452/454 (M+H)

I-181:5-[2-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.72 (s, 1H), 10.01 (s, 1H), 9.40 (s, 1H),7.87 (s, 1H), 7.22 (d, J=8.3, 3H), 7.17-7.01 (m, 1H), 3.55 (s, 3H), 2.12(s, 3H) ppm; MS (ES) 398/400 (M+H).

I-182:5-[2-(4-Chloro-3-ethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.76 (s, 1H), 10.24 (s, 1H), 9.56 (s, 1H),7.90 (s, 1H), 7.24 (m, 4H), 7.00 (d, J=10.6, 1H), 3.59 (m, 2H), 2.13 (s,3H), 1.18 (t, J=6.9, 3H) ppm; MS (ES) 412/414 (M+H).

I-183:5-[2-(4-Fluoro-3-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.75 (s, 1H), 10.25-10.08 (s br, 1H),9.63-9.49 (s br, 1H), 7.86 (s, 1H), 7.19 (m, 5H), 3.55 (s, 3H), 2.13 (s,3H) ppm; MS (ES) 382 (M+H);

I-184:5-[2-(3,5-Dichloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 402/404 (M+H)

I-185:5-[2-(3-Bromo-5-chloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 448 (M+H)

I-186:5-[2-(3-Chloro-5-fluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.69 (s, 1H), 10.25 (br. s., 1H), 9.50 (br. s.,1H), 7.94 (s, 1H), 7.23-7.44 (m, 3H), 7.06-7.23 (m, 2H), 6.93 (d, J=8.3Hz, 1H), 2.13 (s, 3H) ppm; MS (ES) 386 (M+H);

I-187:3-Chloro-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzonitrile

MS (ES) 393/395 (M+H)

I-188:5-[2-(4-Bromo-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 482/484 (M+H);

I-189:5-[2-(3-Bromo-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 480/482 (M+H);

I-190:N-Cyclobutyl-2-methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide

MS (ES) 445 (M+H);

I-191:5-{2-[3-Chloro-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.57 (s, 1H), 9.02 (s, 1H), 8.40 (s, 1H),8.11 (s, 1H), 7.84 (d, J=6.3, 1H), 7.37 (d, J=9.1, 1H), 7.30-7.19 (m,1H), 6.96 (d, J=9.1, 1H), 6.69-6.40 (m, 1H), 4.26-4.00 (m, 2H), 3.63 (m,4H), 3.02-2.81 (m, 2H), 2.87-2.60 (m, 4H), 2.07 (s, 3H) ppm; MS (ES)497/499 (M+H);

I-192:5-{5-Methyl-2-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.02 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.82(s, 1H), 7.49 (d, J=9.0, 2H), 7.41-7.26 (m, 2H), 7.21 (d, J=8.5, 1H),6.76 (d, J=9.0, 2H), 4.09 (t, J=5.3, 2H), 3.76-3.59 (m, 4H), 3.01 (t,J=5.2, 2H), 2.81 (s, 4H), 2.07 (s, 3H) ppm; MS (ES) 463 (M+H);

I-193:5-[2-(2,4-Difluoro-5-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.70 (s, 1H), 9.82 (s, 1H), 9.54 (s, 1H),7.84 (s, 1H), 7.45 (t, J=10.8, 1H), 7.32-7.21 (m, 1H), 7.18 (d, J=5.1,2H), 3.57 (s, 3H), 2.12 (s, 3H) ppm; MS (ES) 400 (M+H);

I-194:5-[2-(3-Chloro-4-ethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.73 (s, 1H), 10.16 (s, 1H), 9.67 (s, 1H),7.86 (s, 1H), 7.53 (s, 1H), 7.22 (m, 3H), 7.08-6.88 (m, 1H), 4.10-3.82(m, 2H), 2.07 (s, 3H), 1.44-1.06 (m, 3H) ppm; MS (ES) 412/414 (M+H);

I-195:5-[2-(4-Cyclobutylmethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.81 (s, 1H), 10.20 (s, 1H), 9.74 (s, 1H),7.81 (s, 1H), 7.35-7.10 (m, 4H), 6.82 (d, J=8.8, 2H), 3.87 (d, J=6.8,2H), 2.78-2.59 (m, 1H), 2.12 (s, 3H), 2.09-1.96 (m, 2H), 1.85 (m, 4H)ppm; MS (ES) 418 (M+H);

I-196:5-[2-(4-Isobutoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.81 (s, 1H), 10.25 (s, 1H), 9.70 (s, 1H),7.81 (s, 1H), 7.24 (m, 3H), 6.81 (m, 2H), 3.66 (m, 2H), 2.10 (s, 3H),1.97 (m, 1H), 0.94 (m, 6H) ppm; MS (ES) 406 (M+H);

I-197:5-{5-Methyl-2-[4-(3-methyl-butoxy)-phenylamino]-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.81 (s, 2H), 10.19 (s, 1H), 9.69 (s, 1H),7.82 (s, 1H), 7.35-7.14 (m, 4H), 6.82 (d, J=8.9, 2H), 3.91 (t, J=6.6,2H), 2.11 (s, 3H), 1.88-1.63 (m, 1H), 1.56 (q, J=6.6, 2H), 0.90 (d,J=6.6, 6H) ppm; MS (ES) 420 (M+H);

I-198:5-[2-(3-Chloro-4-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-onetrifluoroacetic acid salt

¹H NMR (DMSO, 300 MHz): δ 11.80 (s, 1H), 11.07 (s, 1H), 9.81 (s, 1H),7.98 (s, 1H), 7.83 (s, 1H), 7.59 (d, J=8.8, 1H), 7.43-7.25 (m, 2H), 7.20(s, 1H), 7.12 (d, J=8.5, 1H), 2.13 (s, 3H) ppm; MS (ES) 436/438 (M+H);

I-199:5-[2-(3-Fluoro-5-methyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.74 (s, 1H), 10.32 (s, 1H), 9.70 (s, 1H),7.92 (s, 1H), 7.31 (d, J=8.5, 1H), 7.18 (d, J=9.6, 2H), 6.96 (s, 1H),6.62 (d, J=10.0, 1H), 2.13 (s, 3H), 2.10 (s, 3H) ppm; MS (ES) 366 (M+H);

I-200:5-[2-(2,4-Difluoro-3-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO-d₆) δ: 11.84 (s, 1H), 10.33 (s, 1H), 9.77 (s, 1H), 7.89 (s,1H), 7.55-6.94 (m, 5H), 3.82 (s, 3H), 2.12 (s, 3H).ppm; MS (ES) 400(M+H);

I-201:5-(2-(4-(1-(azetidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₄N₆O₂. MS (ESI) m/z 417.01 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.91(s, 1H, NH), 8.30 (s, 1H, NH), 8.17 (s, 1H, NH), 7.75 (s, 1H, ArH),7.65-7.52 (m, 2H, ArH), 7.38-7.27 (m, 2H, ArH), 7.22 (s, 1H, ArH), 7.01(t, J=8.3, 1H, ArH), 6.78 (d, J=8.5, 1H, ArH), 3.63-2.85 (m, 5H, CH,2CH₂), 2.05 (s, 3H, CH₃), 1.95-1.75 (m, 2H, CH₂), 1.05 (d, J=6.6, 3H,CH₃).

I-202:5-(2-(4-(1-(cyclopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₄N₆O₂. MS (ESI) m/z 417.03 (M+1)⁺.

I-203:5-(5-methyl-2-(4-(1-(pyrrolidin-1-yl)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₆N₆O₂. MS (ESI) m/z 431.12 (M+1)⁺.

I-204:5-(5-methyl-2-(4-(1-morpholinoethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₆N₆O₃. MS (ESI) m/z 447.13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.80(s, 1H, NH), 8.21 (s, 1H, NH), 8.12 (s, 1H, NH), 7.77 (s, 1H, ArH), 7.64(d, J=2.5, 1H, ArH), 7.55 (d, J=8.5, 2H, ArH), 7.16 (dd, J=9.6, 2.3, 1H,ArH), 6.99 (d, J=8.5, 2H, ArH), 6.79 (d, J=8.6, 1H, ArH), 3.63-3.23 (m,5H, CH, 2CH₂), 2.31-2.18 (m, 4H, 2CH₂), 2.07 (s, 3H, CH₃), 1.22 (d,J=6.7, 3H, CH₃).

I-205:5-(2-(4-(1-(3-(diethylamino)pyrrolidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₈H₃₅N₇O₂. MS (ESI) m/z 502.19 (M+1)⁺.

I-206:5-(2-(4-(1-(benzylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₇H₂₆N₆O₂. MS (ESI) m/z 467.03 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.32(s, 1H, NH), 8.15 (s, 1H, NH), 7.33-7.15 (m, 13H, ArH), 4.22 (s, 2H,CH₂), 3.48 (m, 1H, CH), 1.84 (s, 3H, CH₃), 1.22 (d, J=6.6, 3H, CH₃).

I-207:5-(2-(4-(1-(isopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₆N₆O₂. MS (ESI) m/z 419.04 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.13(s, 1H, NH), 8.35 (s, 1H, NH), 8.27 (s, 1H, NH), 7.86 (s, 1H, ArH), 7.65(d, J=8.4, 2H, ArH), 7.42 (s, 1H, ArH), 7.32 (d, J=8.7, 1H, ArH),7.27-7.16 (m, 3H, ArH), 4.16 (m, 1H, CH), 2.08 (s, 3H, CH₃), 1.42 (m,5H, 2CH₂, CH), 1.11 (d, J=6.3, 3H, CH₃).

I-208:5-(5-methyl-2-(3-(1-(propylamino)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₆N₆O₂. MS (ESI) m/z 419.06 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.03(s, 1H, NH), 8.33 (s, 1H, NH), 8.24 (s, 1H, NH), 7.86 (s, 1H, ArH),7.60-7.53 (m, 2H, ArH), 7.37 (d, J=1.7, 1H, ArH), 7.31 (dd, J=8.6, 2.1,1H, ArH), 7.20 (d, J=8.6, 1H, ArH), 7.16-7.06 (m, 1H, ArH), 6.88 (d,J=7.5, 1H, ArH), 3.54 (m, 1H, CH), 2.34 (m, 2H, CH₂), 2.08 (s, 3H, CH₃),1.40 (m, 2H, CH₂), 1.27 (d, J=6.6, 3H, CH₃), 0.79 (t, J=7.4, 3H, CH₃).

I-209:5-(2-(3-(1-(isopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₆N₆O₂. MS (ESI) m/z 419.05 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.04(s, 1H, NH), 8.34 (s, 1H, NH), 8.24 (s, 1H, NH), 7.86 (s, 1H, ArH),7.67-7.48 (m, 2H, ArH), 7.42-7.03 (m, 4H, ArH), 6.90 (d, J=7.6, 1H,ArH), 3.71 (m, 1H, CH), 2.66-2.42 (m, 1H, CH), 2.34 (m, 2H, CH₂), 2.08(s, 3H, CH₃), 1.27 (d, J=6.6, 3H, CH₃), 0.95 (m, 6H, 2CH₃).

I-210:5-(2-(3-(1-(isopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₄N₆O₂. MS (ESI) m/z 417.04 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.92(s, 1H, NH), 8.32 (s, 1H, NH), 8.15 (s, 1H, NH), 7.86 (s, 1H, ArH), 7.51(d, J=9.5, 2H, ArH), 7.31 (d, J=7.0, 2H, ArH), 7.21 (d, J=9.2, 1H, ArH),7.05 (t, J=7.8, 1H, ArH), 6.83 (d, J=7.6, 1H, ArH), 3.47 (m, 1H, CH),2.07 (s, 3H, CH₃), 1.90-1.74 (m, 1H, CH), 1.13 (d, J=6.6, 3H, CH₃), 0.21(m, 4H, 2CH₂).

I-211:5-(2-(3-(1-(azetidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₄N₆O₂. MS (ESI) m/z 417.03 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.94(s, 1H, NH), 8.33 (s, 1H, NH), 8.18 (s, 1H, NH), 7.85 (s, 1H, ArH),7.54-7.43 (m, 2H, ArH), 7.31 (s, 1H, ArH), 7.28-7.23 (m, 2H, ArH), 7.02(t, J=7.8, 1H, ArH), 6.74 (d, J=7.5, 1H, ArH), 3.53 (m, 1H, CH), 2.98(m, 4H, 2CH₂), 2.04 (s, 3H, CH₃), 1.95-1.78 (m, 2H, CH₂), 0.95 (d,J=6.6, 3H, CH₃).

I-212:5-(5-methyl-2-(3-(1-(pyrrolidin-1-yl)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₆N₆O₂. MS (ESI) m/z 431.12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.94(s, 1H, NH), 8.33 (s, 1H, NH), 8.17 (s, 1H, NH), 7.85 (s, 1H, ArH), 7.50(d, J=8.3, 2H, ArH), 7.25-7.15 (m, 3H, ArH), 7.03 (t, J=7.8, 1H, ArH),6.79 (d, J=10.5, 1H, ArH), 3.51 (m, 1H, CH), 2.98 (m, 4H, 2CH₂),2.54-2.38 (m, 4H, 2CH₂), 2.07 (s, 3H, CH₃), 1.67-1.51 (m, 4H, 2CH₂),0.95 (d, J=6.6, 3H, CH₃).

I-213:5-(2-(3-(1-(benzylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₇H₂₆N₆O₂. MS (ESI) m/z 467.04 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.99(s, 1H, NH), 8.31 (s, 1H, NH), 8.19 (s, 1H, NH), 7.86 (s, 1H, ArH), 7.61(s, 1H, ArH), 7.55 (s, 1H, ArH), 7.35 (s, 1H, ArH), 7.31-7.20 (m, 5H,ArH), 7.18 (m, 1H, ArH), 7.15 (m, 1H, ArH), 7.09 (t, J=7.9, 1H, ArH),6.89 (d, J=7.5, 1H, ArH), 3.58 (m, 1H, CH), 3.55 (s, 2H, CH₂), 2.08 (s,3H, CH₃), 1.23 (d, J=6.6, 3H, CH₃).

I-214:5-(2-(3-(1-(3-(diethylamino)pyrrolidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₈H₃₅N₇O₂. MS (ESI) m/z 502.12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.96(s, 1H, NH), 8.33 (s, 1H, NH), 8.18 (s, 1H, NH), 7.85 (s, 1H, ArH),7.53-7.44 (m, 2H, ArH), 7.33 (s, 1H, ArH), 7.26 (d, J=1.8, 1H, ArH),7.23 (s, 1H, ArH), 7.04 (t, J=7.9, 1H, ArH), 6.76 (d, J=7.6, 1H, ArH),3.57-3.40 (m, 1H, CH), 2.76 (dd, J=14.5, 7.3, 4H, 2CH₂), 2.35 (d, J=5.8,3H, CH₂, CH), 2.21 (d, J=8.3, 1H, CH), 2.07 (s, 3H, CH₃), 1.98-1.84 (m,2H, CH₂), 1.78-1.62 (m, 1H, CH), 1.16 (d, J=6.3, 3H, CH₃), 1.01 (m, 6H,2CH₃).

I-215:5-(5-methyl-2-(3-(1-(piperidin-1-yl)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₂₈N₆O₂. MS (ESI) m/z 444.95 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.22(s, 1H, NH), 8.35 (s, 1H, NH), 8.21 (s, 1H, NH), 7.96 (d, J=7.9, 1H,ArH), 7.89 (s, 1H, ArH), 7.46-7.38 (m, 2H, ArH), 7.37-7.30 (m, 1H, ArH),7.27 (d, J=7.6, 1H, ArH), 7.22 (s, 1H, ArH), 7.18 (s, 1H, ArH),3.57-3.45 (m, 1H, CH), 2.52-2.40 (m, 4H, 2CH₂), 2.09 (s, 3H, CH₃),1.46-1.36 (m, 6H, 3CH₂), 1.15 (d, J=6.7, 3H, CH₃).

I-216:5-(2-(3-(1-(diethylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₈N₆O₂. MS (ESI) m/z 433.07 (M+1)⁺.

I-217:5-(5-methyl-2-(3-(1-morpholinoethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₆N₆O₃. MS (ESI) m/z 447.06 (M+1)⁺.

I-218:N-cyclobutyl-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2-(trifluoromethyl)benzamide

C₂₄H₂₁F₃N₆O₃. MS (ESI) m/z 499.07 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.66(s, 1H, NH), 10.17 (s, 1H, NH), 8.54 (s, 1H, NH), 8.52 (s, 1H, NH), 7.93(s, 1H, ArH), 7.85 (s, 1H, ArH), 7.74 (d, J=9.9, 1H, ArH), 7.29 (dd,J=13.6, 8.1, 2H, ArH), 7.23-7.14 (m, 2H, ArH), 4.28 (m, 1H, CH),2.16-2.09 (m, 2H, CH₂), 2.13 (s, 3H, CH₃), 2.02-1.82 (m, 2H, CH₂),1.67-1.60 (m, 2H, CH₂).

I-219:4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-N-phenyl-2-(trifluoromethyl)benzamide

C₂₆H₁₉F₃N₆O₃. MS (ESI) m/z 521.10 (M+1)⁺.

I-220:N-cyclopropyl-2-methoxy-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide

C₂₃H₂₂N₆O₄. MS (ESI) m/z 446.46 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.72(s, 1H, NH), 10.06 (s, 1H, NH), 9.61 (s, 1H, NH), 7.87 (s, 1H, ArH),7.33-6.99 (m, 4H, ArH), 6.93 (d, J=8.2, 1H, ArH), 6.59 (d, J=9.7, 1H,ArH), 3.54 (m, 3H, CH₃), 2.48 (m, 1H, CH), 2.12 (s, 3H, CH₃), 1.37-1.20(m, 4H, 2CH₂).

I-221:2-methoxy-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-N-phenylbenzamide

C₂₆H₂₂N₆O₄. MS (ESI) m/z 482.49 (M+1)⁺.

I-222:4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2-(trifluoromethyl)benzoicacid

C₂₀H₁₄F₃N₅O₄. MS (ESI) m/z 446.01 (M+1)⁺.

I-223:N-cyclopropyl-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2-(trifluoromethyl)benzamide

C₂₃H₁₉F₃N₆O₄. MS (ESI) m/z 485.08 (M+1)⁺.

I-224:-(2-(3-isobutoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₂F₃N₅O₃. MS (ESI) m/z 474.06 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.31(s, 1H, NH), 8.40 (s, 1H, NH), 7.92 (s, 1H, NH), 7.61 (s, 1H, ArH), 7.54(s, 1H, ArH), 7.34-7.22 (m, 2H, ArH), 7.18 (d, J=8.4, 2H, ArH), 6.61 (s,1H, ArH), 3.56 (d, J=6.6, 2H, CH₂), 2.09 (s, 3H, CH₃), 1.97-1.81 (m, 1H,CH), 0.87 (d, J=6.6, 6H, 2CH₃).

I-225:5-(2-(3-(cyclopropylmethoxy)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₀F₃N₅O₃. MS (ESI) m/z 472.05 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.27(s, 1H, NH), 8.13 (s, 1H, NH), 7.92 (s, 1H, NH), 7.60 (s, 1H, ArH), 7.53(s, 1H, ArH), 7.31-7.21 (m, 2H, ArH), 6.72 (s, 2H, ArH), 6.45-6.13 (m,1H, ArH), 3.76-3.62 (m, 2H, CH₂), 2.48 (m, 1H, CH), 2.09 (s, 3H, CH₃),0.52 (d, J=7.2, 2H, CH₃), 0.22 (d, J=5.9, 2H, CH₃).

I-226:5-(2-(3-cyclobutoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₀F₃N₅O₃. MS (ESI) m/z 472.09 (M+1)⁺.

I-227:5-(2-(3-(cyclobutylmethoxy)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₂F₃N₅O₃. MS (ESI) m/z 486.11 (M+1)⁺.

I-228:5-(2-(3-deuteratedmethoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₃D₃F₃N₅O₃. MS (ESI) m/z 435.13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ8.42 (s, 1H, NH), 8.13 (s, 1H, NH), 7.91 (s, 1H, NH), 7.57 (d, J=7.1,2H, ArH), 7.30-7.13 (m, 4H, ArH), 6.62 (s, 1H, ArH), 2.08 (s, 3H, CH₃).

I-229:5-(2-(3-acetyl-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₁H₁₉N₅O₄. MS (ESI) m/z 406.12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.19(s, 1H, NH), 8.39 (s, 1H, NH), 8.21 (s, 1H, NH), 7.90 (s, 1H, ArH), 7.75(s, 1H, ArH), 7.66 (s, 1H, ArH), 7.33-7.26 (m, 2H, ArH), 7.19-7.16 (m,1H, ArH), 6.90 (s, 1H, ArH), 3.64 (s, 3H, CH₃), 2.37 (s, 3H, CH₃), 2.08(s, 3H, CH₃).

I-230:5-(2-(3-chloro-4-fluoro-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₁₉H₁₂Cl_(F4)N₅O₂. MS (ESI) m/z 453.96 (M+1)⁺.

I-231:5-(2-(3-(1-(isopropylamino)ethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₈N₆O₃. MS (ESI) m/z 449.13 (M+1)⁺.

I-232:5-(2-(3-methoxy-5-(1-(propylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₈N₆O₃. MS (ESI) m/z 449.07 (M+1)⁺.

I-233:5-(2-(3-(1-(cyclopropylamino)ethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₆N₆O₃. MS (ESI) m/z 447.20 (M+1)⁺.

I-234:5-(2-(3-methoxy-5-(1-(pyrrolidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₂₈N₆O₃. MS (ESI) m/z 461.12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.25(s, 1H, NH), 8.30 (s, 1H, NH), 8.21 (s, 1H, NH), 7.90 (s, 1H, ArH),7.33-7.11 (m, 2H, ArH), 6.99-6.69 (m, 3H, ArH), 6.47 (s, 1H, ArH), 3.79(q, J=7.7, 1H, CH), 3.71 (s, 3H, CH₃), 2.13 (s, 3H, CH₃), 2.54-2.06 (m,8H, 4-CH₂), 1.44 (s, 3H, CH₃).

I-235:5-(2-(3-(1-(azetidin-1-yl)ethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₆N₆O₃. MS (ESI) m/z 447.42 (M+1)⁺.

I-236:5-(2-(3-methoxy-5-(1-(methylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₂H₂₄N₆O₃. MS (ESI) m/z 421.14 (M+1)⁺.

I-237:5-(2-(3-(difluoromethyl)-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₇F₂N₅O₂. MS (ESI) m/z 398.08 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.17(s, 1H, NH), 8.40 (s, 1H, NH), 8.11 (s, 1H, NH), 7.88 (s, 1H, ArH), 7.60(d, J=13.3, 2H, ArH), 7.30-7.20 (m, 3H, ArH), 6.78 (s, 1H, ArH), 6.71(t, J=61.7, 2H, CH), 2.10 (s, 3H, CH₃), 2.08 (s, 3H, CH₃).

I-238:5-(2-(3-(fluoromethyl)-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₈FN₅O₂. MS (ESI) m/z 380.08 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.04(s, 1H, NH), 8.37 (s, 1H, NH), 8.11 (s, 1H, NH), 7.87 (s, 1H, ArH), 7.45(d, J=8.4, 2H, ArH), 7.34-7.18 (m, 3H, ArH), 6.65 (s, 1H, ArH), 5.12 (d,J=53.3, 2H, CH₂), 2.47 (s, 3H, CH₃), 2.08 (s, 3H, CH₃).

I-239:5-(5-methyl-2-(4-methyl-3-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.63 (s, 1H), 9.34 (s, 1H), 8.40 (s, 1H), 8.18(d, J=1.7, 1H), 8.05 (dd, J=8.4, 1.9, 1H), 7.93 (s, 1H), 7.44 (dd,J=8.6, 1.9, 1H), 7.39 (s, 1H), 7.26 (d, J=8.6, 1H), 7.22 (d, J=8.4, 1H),3.16 (s, 3H), 2.56 (s, 3H), 2.15 (s, 3H); LRMS (M+) m/z 426.01.

I-240:5-(2-(3-fluoro-5-morpholinophenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 7.92(s, 1H), 7.32 (br s, 1H), 7.26-7.23 (m, 2H), 7.16 (d, J=12.1, 1H), 6.96(s, 1H), 6.27 (d, J=12.1, 1H), 3.67-3.64 (m, 4H), 2.97-2.94 (m, 4H),2.14 (s, 3H); LRMS (M+) m/z 437.05.

I-241:5-(2-(3-fluoro-5-(4-methylpiperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.04 (s, 1H), 8.44 (s, 1H), 7.92(s, 1H), 7.33 (s, 1H), 7.30-7.22 (m, 2H), 7.18 (d, J=12.1, 1H), 6.95 (s,1H), 6.27 (d, J=12.1, 1H), 3.08-3.04 (m, 4H), 2.56-2.53 (m, 4H,overlapped with DMSO peaks), 2.35 (s, 3H), 2.14 (s, 3H); LRMS (M+) m/z450.06.

I-242:5-(2-(4-fluoro-3-(methylsulfonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 10.14 (s, 1H), 9.36 (s, 1H),8.00-7.91 (m, 3H), 7.41 (t, J=9.3, 1H), 7.34-7.21 (m, 3H), 3.31 (s, 3H),2.19 (s, 3H); LRMS (M+) m/z 429.99.

I-243:3-(5-methyl-4-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzenesulfonamide

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 10.09 (br s, 1H), 9.33 (br s,1H), 7.93-7.91 (m, 2H), 7.78 (s, 1H), 7.48 (d, J=7.6, 1H), 7.39-7.34 (m,3H), 7.14 (s, 1H), 7.12 (s, 1H), 2.33 (s, 3H), 2.19 (s, 3H); LRMS (M+)m/z 426.94.

I-244:7-methyl-5-(5-methyl-2-(3-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.63 (s, 1H), 10.01 (s, 1H), 9.18 (s, 1H),8.01 (d, J=7.3, 1H), 7.96-7.94 (m, 2H), 7.54 (d, J=8.0, 1H), 7.44 (t,J=8.0, 1H), 7.13 (br s, 2H), 3.14 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H);LRMS (M+) m/z 426.01.

I-245:5-(2-(4-fluoro-3-(methylsulfonyl)phenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 10.08 (br s, 1H), 9.26 (br s,1H), 8.05-8.00 (m, 1H), 7.93-7.90 (m, 2H), 7.37 (t, J=9.3, 1H), 7.13 (s,1H), 7.11 (s, 1H), 3.30 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H); LRMS (M+)m/z 444.01.

I-246:5-(5-methyl-2-(3-(pyrrolidine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 10.19 (s, 1H), 9.71 (s, 1H),7.94 (s, 1H), 7.66 (s, 1H), 7.50 (d, J=8.7, 1H), 7.37-7.24 (m, 5H), 3.46(t, J=6.5, 2H), 3.26 (t, J=6.5, 2H), 2.20 (s, 3H), 1.90-1.77 (m, 4H);LRMS (M+) m/z 431.06.

I-247:5-(5-methyl-2-(4-(pyrrolidine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.81 (s, 1H), 10.13 (s, 1H), 9.62 (s, 1H),7.95 (s, 1H), 7.53-7.50 (m, 2H), 7.45-7.36 (m, 3H), 7.29 (br s, 1H),7.24 (dd, J=8.4, 2.0, 1H), 3.48 (t, J=6.4, 2H), 3.39 (t, J=6.4, 2H),2.20 (s, 3H), 1.92-1.82 (m, 4H); LRMS (M+) m/z 431.05.

I-248:3-(4-(7-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)-5-methylpyrimidin-2-ylamino)benzenesulfonamide

¹H NMR (300 MHz, DMSO) δ 12.04 (s, 1H), 10.03 (br s, 1H), 9.23 (br s,1H), 7.99 (br s, 1H), 7.96-7.93 (m, 2H), 7.56-7.42 (m, 3H), 7.36 (br s,2H), 7.19 (d, J=1.5, 1H), 2.19 (s, 3H); LRMS (M+) m/z 431.02.

I-249:7-fluoro-5-(5-methyl-2-(3-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.03 (s, 1H), 10.03 (br s, 1H), 9.16 (br s,1H), 8.08 (s, 1H), 8.04-8.02 (m, 2H), 7.58-7.50 (m, 3H), 7.19 (d, J=1.7,1H), 3.17 (s, 3H), 2.19 (s, 3H); LRMS (M+) m/z 430.03.

I-250:7-fluoro-5-(2-(4-fluoro-3-(methylsulfonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.01 (s, 1H), 10.06 (br s, 1H), 9.20 (br s,1H), 8.05-8.00 (m, 3H), 7.49-7.41 (m, 2H), 7.20 (d, J=1.5, 1H), 3.31 (s,3H), 2.18 (s, 3H); LRMS (M+) m/z 448.01.

I-251:7-fluoro-5-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.03 (s, 1H), 10.00 (br s, 1H), 9.31 (br s,1H), 8.01 (br s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.38 (d, J=12.3, 1H),7.15 (s, 1H), 6.86 (s, 1H), 3.76 (s, 3H), 2.18 (s, 3H); LRMS (M+) m/z450.05.

I-252:3-methoxy-N,N-dimethyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.18 (br s, 1H), 9.71 (br s,1H), 7.95 (s, 1H), 7.31 (d, J=8.5, 1H), 7.24 (br s, 1H), 7.21 (br d,J=8.5, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.64 (s, 1H), 3.68 (s, 3H), 2.98(s, 3H), 2.84 (s, 3H), 2.19 (s, 3H); LRMS (M+) m/z 435.04.

I-253:5-(2-(3-methoxy-5-(pyrrolidine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 10.30 (br s, 1H), 9.78 (br s,1H), 7.96 (s, 1H), 7.30 (d, J=8.4, 1H), 7.25 (br s, 1H), 7.22 (br d,J=8.4, 1H), 7.17 (s, 1H), 7.11 (br s, 1H), 6.76 (br s, 1H), 3.69 (s,3H), 3.45 (t, J=6.5, 2H), 3.27 (t, J=6.5, 2H), 2.20 (s, 3H), 1.91-1.75(m, 4H); LRMS (M+) m/z 461.09.

I-254:5-(2-(3-methoxy-5-(morpholine-4-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 10.07 (br s, 1H), 9.57 (br s,1H), 7.95 (s, 1H), 7.31 (d, J=8.4, 1H), 7.25-7.18 (m, 3H), 7.06 (s, 1H),6.63 (s, 1H), 3.78-3.28 (m, 8H, overlapped), 3.68 (s, 3H, overlapped),2.19 (s, 3H); LRMS (M+) m/z 477.10.

I-255:5-(2-(3-methoxy-5-(4-methylpiperazine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.42 (br s, 1H), 10.07 (br s,1H), 9.64 (br s, 1H), 8.00 (s, 1H), 7.31 (d, J=8.4, 1H), 7.25-7.21 (m,3H), 7.06 (s, 1H), 6.68 (s, 1H), 4.01-3.01 (m, 8H, overlapped), 3.67 (s,3H, overlapped), 2.86 (s, 3H), 2.19 (s, 3H); LRMS (M+) m/z 490.10.

I-256:5-(5-methyl-2-(3-(morpholine-4-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 10.30 (s, 1H), 9.71 (s, 1H),7.96 (s, 1H), 7.54-7.51 (m, 2H), 7.37-7.31 (m, 2H), 7.25-7.23 (m, 2H),7.12 (d, J=7.6, 1H), 3.62-3.26 (m, 8H), 2.20 (s, 3H); LRMS (M+) m/z447.09.

I-257:5-(5-methyl-2-(4-(morpholine-4-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.83 (s, 1H), 10.38 (s, 1H), 9.71 (s, 1H),7.98 (s, 1H), 7.55-7.52 (m, 2H), 7.39 (d, J=8.5, 1H), 7.33-7.30 (m, 3H),7.25 (br d, J=8.5, 1H), 3.63-3.51 (m, 8H), 2.20 (s, 3H); LRMS (M+) m/z447.03.

I-258:5-(2-(4-methoxy-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.84 (s, 1H), 10.06 (s, 1H), 9.79 (s, 1H),7.83 (s, 1H), 7.35 (d, J=8.2, 1H), 7.27-7.23 (m, 2H), 7.17-7.14 (m, 2H),6.91 (br d, J=8.2, 1H), 3.79 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H); LRMS(M+) m/z 378.05.

I-259:5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 9.85 (s, 1H), 9.39 (s, 1H), 8.15(d, J=4.4, 1H), 7.47 (dd, J=8.6, 1.5, 1H), 7.39-7.27 (m, 4H), 6.87 (d,J=8.6, 1H), 3.78 (s, 3H), 2.06 (s, 3H); LRMS (M+) m/z 378.05.

I-260:2-methoxy-N,N-dimethyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide

¹H NMR (300 MHz, DMSO) δ 11.80 (s, 1H), 9.99 (s, 1H), 9.68 (s, 1H), 7.87(s, 1H), 7.38 (br d, J=8.9, 1H), 7.30 (d, J=8.6, 1H), 7.25-7.20 (m, 3H),7.06 (d, J=8.9, 1H), 3.80 (s, 3H), 2.99 (s, 3H), 2.71 (s, 3H), 2.18 (s,3H); LRMS (M+) m/z 435.11.

I-261:5-(2-(4-methoxy-3-(pyrrolidine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.82 (s, 1H), 9.81 (br s, 1H), 9.50 (br s,1H), 7.87 (s, 1H), 7.40 (br d, J=8.8, 1H), 7.31 (d, J=2.9, 1H),7.27-7.22 (m, 3H), 7.05 (d, J=8.8, 1H), 3.80 (s, 3H), 3.46 (t, J=6.6,2H), 3.05 (t, J=6.6, 2H), 2.17 (s, 3H), 1.92-1.74 (m, 4H); LRMS (M+) m/z461.11.

I-262:5-(2-(4-methoxy-3-(morpholine-4-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 9.88 (br s, 1H), 9.52 (br s,1H), 7.87 (s, 1H), 7.45 (dd, J=8.7, 1.9, 1H), 7.33-7.22 (m, 4H), 7.04(d, J=8.7, 1H), 3.81 (s, 3H), 3.65-3.08 (m, 8H), 2.18 (s, 3H); LRMS (M+)m/z 477.10.

I-263:5-(2-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.96 (br s, 1H), 9.59 (br s,1H), 7.91 (s, 1H), 7.53 (br d, J=8.7, 1H), 7.34-7.25 (m, 4H), 7.07 (d,J=8.7, 1H), 4.60-3.10 (m, 8H, overlapped), 3.83 (s, 3H, overlapped),2.89 (br s, 3H), 2.18 (s, 3H); LRMS (M+) m/z 490.10.

I-264:5-(2-(3-methyl-4-trideuteromethoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.83 (s, 1H), 9.99 (s, 1H), 9.78 (s, 1H), 7.81(s, 1H), 7.35 (d, J=9.0, 1H), 7.27-7.24 (m, 2H), 7.17-7.14 (m, 2H), 6.91(br d, J=9.0, 1H), 2.18 (s, 3H), 2.02 (s, 3H); LRMS (M+) m/z 381.10.

I-265:5-(2-(3-chloro-4-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.89 (br s, 1H), 9.57 (br s,1H), 7.92 (s, 1H), 7.48 (s, 1H), 7.36 (d, J=8.3, 1H), 7.24-7.18 (m, 3H),3.71 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H); LRMS (M+) m/z 411.97.

I-266:5-(2-(3-methyl-5-trideuteromethoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.93 (br s, 1H), 9.72 (br s,1H), 7.90 (s, 1H), 7.35 (d, J=8.3, 1H), 7.25-7.22 (m, 2H), 6.84 (s, 1H),6.81 (s, 1H), 6.50 (s, 1H), 3.43 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H);LRMS (M+) m/z 381.10.

I-267:2-methoxy-N,N-dimethyl-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.49 (s, 1H), 9.74 (s, 1H),7.92 (s, 1H), 7.30-7.14 (m, 3H), 7.04 (d, J=8.8, 1H), 7.03 (app s, 2H),3.45 (s, 3H), 2.92 (s, 3H), 2.70 (s, 3H), 2.14 (s, 3H).

I-268:5-(2-(3-methoxy-4-(pyrrolidine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 10.33 (s, 1H), 9.66 (s, 1H),7.90 (s, 1H), 7.30-7.17 (m, 3H), 7.05 (d, J=5.9, 1H), 7.04 (app s, 2H),3.46 (s, 3H), 3.38 (t, J=6.5, 2H), 3.03 (t, J=6.5, 2H), 2.14 (s, 3H),1.79 (dt, J=18.9, 6.5, 4H).

I-269:5-(2-(3-methoxy-4-(morpholine-4-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 10.26 (s, 1H), 9.65 (s, 1H),7.89 (s, 1H), 7.31-7.16 (m, 3H), 7.07 (d, J=8.5, 1H), 7.06 (app s, 2H),3.57 (br s, 4H), 3.47 (br s, 2H), 3.45 (s, 3H), 3.08 (br s, 2H), 2.14(s, 3H).

I-270:5-(2-(3-methoxy-4-(4-methylpiperazine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.30 (s, 1H), 9.95 (s, 1H),9.48 (s, 1H), 7.94 (s, 1H), 7.29-7.04 (m, 6H), 3.44 (s, 3H), 2.82 (s,3H), 2.13 (s, 3H).

I-271:5-(2-(3-(difluoromethyl)-4-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 9.16 (s, 1H), 8.54 (s, 1H), 7.84(s, 1H), 7.71 (d, J=11.0, 2H), 7.31 (d, J=8.4, 1H), 7.31 (s, 1H), 7.20(d, J=8.4, 1H), 6.94 (t, J=55.4, 1H), 6.93 (s, 1H), 3.76 (s, 3H), 2.08(s, 3H).

I-272:5-(2-(4-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 8.93 (s, 1H), 8.49 (s, 1H), 7.80(s, 1H), 7.46 (d, J=8.9, 2H), 7.31 (d, J=9.0, 2H), 7.30 (s, 1H), 7.21(d, J=9.0, 1H), 6.74 (d, J=8.9, 2H), 3.67 (s, 3H), 2.07 (s, 3H).

I-273:5-(2-(3-(difluoromethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 10.12 (s, 1H), 9.56 (s, 1H),7.89 (s, 1H), 7.29-7.11 (m, 5H), 6.76 (t, J=55.9, 1H), 6.73 (s, 1H),3.62 (s, 3H), 2.13 (s, 3H).

I-274:5-(2-(3-(fluoromethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.17 (s, 1H), 9.68 (s, 1H),7.88 (s, 1H), 7.28 (d, J=8.6, 1H), 7.18 (s, 1H), 7.16 (d, J=8.6, 1H),7.02 (s, 1H), 6.98 (s, 1H), 6.64 (s, 1H), 5.25 (s, 1H), 5.09 (s, 1H),3.60 (s, 3H), 2.13 (s, 3H).

I-275:N2-[4-(4,4-difluoropiperidinyl)-3-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.85(s, 1H), 7.64 (d, J=15.3, 1H), 7.25 (m, 3H), 7.18 (d, J=10.8, 1H), 6.88(t, J=9.4, 1H), 2.99 (t, 4H), 2.08 (s, 3H), 2.08 (m, 4H); ¹⁹F NMR (282MHz, DMSO) δ −111.68, −138.03; LCMS: purity: 97.23%; MS (m/e): 471.27(M+H).

I-276:N2-[4-(4,4-difluoropiperidinyl)-3-trifluoromethyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.51 (s, 1H), 9.28 (s, 1H), 8.44 (s, 1H), 7.95(s, 1H), 7.88 (s, 1H), 7.80 (d, 1H), 7.36 (d, J=8.4, 1H), 7.27 (m, 2H),7.19 (d, J=9.3, 1H), 2.88 (t, 4H), 2.09 (s, 3H), 2.03 (m, 4H); ¹⁹F NMR(282 MHz, DMSO) δ −75.78; LCMS: purity: 89.60%; MS (m/e): 521.31 (M+H).

I-277:N2-[3-chloro-4-(4,4-difluoropiperidinyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 9.05 (s, 1H), 8.37 (s, 1H), 7.85(m, 2H), 7.37 (d, J=9.0, 1H), 7.23 (m, 3H), 6.99 (d, J=9.0, 1H), 2.95(t, J=5.1, 4H), 2.08 (s, 3H), 2.08 (m, 4H); LCMS: purity: 93.39%; MS(m/e): 487.23 (M+H).

I-278:N2-[3-chloro-4-(4-ethylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.55 (br, 1H), 9.02 (s, 1H), 8.37 (s, 1H),7.83 (d, J=6.6, 2H), 7.37 (d, J=9.0, 1H), 7.22 (m, 3H), 6.93 (d, J=9.6,1H), 2.87 (s, 4H), 2.08 (s, 3H), 1.03 (t, J=6.9, 3H); LCMS: purity:89.90%; MS (m/e): 480.29 (M+H).

I-279:N2-[4-(4,4-difluoropiperidinyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (br, 1H), 8.73 (s, 1H), 8.25 (s, 1H),7.80 (s, 1H), 7.46 (d, J=7.8, 2H), 7.32 (d, J=9.9, 2H), 7.20 (d, J=7.8,1H), 6.79 (d, J=8.1, 2H), 3.16 (m, 4H), 2.06 (s, 3H), 2.03 (m, 4H); ¹⁹FNMR (282 MHz, DMSO) δ −111.17; LCMS: purity: 97.36%; MS (m/e): 453.23(M+H).

I-280:N2-(3,5-dimethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.51 (s, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 7.85(s, 1H), 7.29 (s, 1H), 7.27 (d, J=11.1, 1H), 7.17 (d, J=9.3, 1H), 6.89(d, J=2.1, 2H), 5.96 (s, 1H), 3.56 (s, 6H), 2.08 (s, 3H); LCMS: purity:91.13%; MS (m/e): 394.24 (M+H).

I-281:N2-[3-fluoro-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 9.57 (br, 1H), 7.86 (s, 1H),7.49 (d, 1H), 7.27 (d, J=7.2, 1H), 7.20 (m, 2H), 7.07 (d, 1H), 6.98 (t,J=9.0, 1H), 3.48 (d, J=10.5, 2H), 3.34 (d, J=12.0, 2H), 3.20 (d, 2H),2.93 (d, J=12.3, 2H), 2.86 (s, 3H), 2.12 (s, 3H); LCMS: purity: 82.99%;MS (m/e): 450.26 (M+H).

I-282:N2-[3,5-difluoro-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.77 (br, 1H), 9.53 (br, 1H),9.03 (br, 1H), 7.90 (s, 1H), 7.28-7.13 (m, 5H), 3.43 (d, J=11.1, 2H),3.24 (d, J=12.3, 2H), 3.15 (br, 4H), 2.84 (d, J=3.6, 3H), 2.11 (s, 3H);LCMS: purity: 92.64%; MS (m/e): 468.29 (M+H).

I-283:N2-[4-chloro-3-(4-ethylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.07 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.88(s, 1H), 7.51 (s, 1H), 7.35-7.18 (m, 4H), 7.08 (d, J=9.0, 1H), 2.72 (br,4H), 2.42 (br, 4H), 2.36 (q, J=7.2, 2H), 2.09 (s, 3H), 1.02 (t, J=7.2,3H); LCMS: purity: 94.40%; MS (m/e): 480.28 (M+H).

I-284:N2-[4-chloro-3-(3,4,5-trimethylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 9.05 (s, 1H), 8.35 (s, 1H), 8.10(s, 1H), 7.87 (s, 1H), 7.32 (m, 3H), 7.20 (d, J=8.7, 1H), 7.13 (d,J=8.4, 1H), 2.09 (s, 3H), 1.23 (br, 6H); LCMS: purity: 80.46%; MS (m/e):494.32 (M+H).

I-285:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[3-(4-propylpiperazino)-4-trifluoromethyl]phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 9.28 (s, 1H), 8.40 (s, 1H), 7.97(s, 1H), 7.88 (s, 2H), 7.28 (m, 3H), 7.19 (d, J=9.3, 1H), 2.94 (br, 8H),2.09 (s, 3H), 1.60 (br, 2H), 0.90 (t, J=7.2, 3H); ¹⁹F NMR (282 MHz,DMSO) δ −75.43; LCMS: purity: 95.71%; MS (m/e): 528.37 (M+H).

I-286:5-methyl-N2-[3-(1,3-oxazol-5-yl)]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 10.03 (br, 1H), 9.49 (br, 1H),8.32 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.40 (m, 2H), 7.32 (m, 2H),7.22 (s, 2H), 7.12 (d, J=9.3, 1H), 2.15 (s, 3H); LCMS: purity: 95.22%;MS (m/e): 401.23 (M+H).

I-287:N2-(3-bromo)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 9.30 (s, 1H), 8.54 (s, 1H), 7.96(s, 1H), 7.88 (s, 1H), 7.45 (d, J=8.1, 1H), 7.23 (m, 2H), 7.05 (t,J=7.8, 1H), 6.96 (m, 2H), 2.10 (s, 3H); LCMS: purity: 97.81%; MS (m/e):412.11 (M+H).

I-288:N2-(4-bromo)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 9.14 (s, 1H), 8.37 (s, 1H), 7.86(s, 1H), 7.62 (d, J=9.0, 2H), 7.26 (m, 5H), 2.09 (s, 3H); LCMS: purity:98.23%; MS (m/e): 412.12 (M+H).

I-289:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[3-(pyridin-4-yl)]phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.58 (d, 2H), 7.99 (br, 1H),7.89 (s, 1H), 7.56 (m, 2H), 7.49 (m, 2H), 7.42 (d, 1H), 7.19 (m, 2H),7.07 (d, 1H), 2.15 (s, 3H); LCMS: purity: 94.63%; MS (m/e): 411.24(M+H).

I-290:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[3-(pyridin-3-yl)]phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 8.62 (s, 1H), 8.53 (d, 1H), 7.84(m, 3H), 7.39 (m, 4H), 7.18 (m, 2H), 7.01 (d, 1H), 2.15 (s, 3H); LCMS:purity: 86.04%; MS (m/e): 411.24 (M+H).

I-291:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[4-(pyridin-3-yl)]phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 8.88 (s, 1H), 8.55 (d, 1H), 8.11(d, 1H), 7.88 (s, 1H), 7.60 (m, 5H), 7.33 (d, 1H), 7.26 (m, 2H), 2.16(s, 3H); LCMS: purity: 94.74%; MS (m/e): 411.21 (M+H).

I-292:N2-[4-methoxy-3-(2-methoxyethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.83(s, 1H), 7.31 (d, J=2.4, 3H), 7.17 (d, J=9.3, 1H), 7.13 (d, J=8.1, 1H),6.72 (d, J=9.0, 1H), 3.69 (t, J=4.8, 2H), 3.66 (s, 3H), 3.50 (d, J=4.2,2H), 3.26 (s, 3H), 2.07 (s, 3H); LCMS: purity: 95.38%; MS (m/e): 438.08(M+H).

I-293:N2-[3-(cyclopropylaminocarbonylmethoxy)-4-methoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 9.86 (br, 1H), 9.54 (br, 1H),7.92 (s, 1H), 7.75 (s, 1H), 7.23 (s, 3H), 6.98 (d, 1H), 6.89 (d, J=9.6,2H), 4.26 (s, 2H), 3.74 (s, 3H), 2.64 (p, J=3.9, 1H), 2.13 (s, 3H), 0.62(q, J=6.0, 2H), 0.44 (q, J=2.7, 2H); LCMS: purity: 96.56%; MS (m/e):477.28 (M+H).

I-294:N2-(3-cyano-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.19 (br, 1H), 9.42 (s, 1H), 8.47 (s, 1H),8.25 (dd, J=2.7, 5.7, 1H), 7.90 (s, 1H), 7.72 (m, J=4.5, 1H), 7.34-7.17(m, 4H), 2.10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −135.29; LCMS: purity:94.39%; MS (m/e): 377.18 (M+H).

I-295:N2-[3-cyano-4-(1H-pyrrol-1-yl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.54 (s, 1H), 8.49 (s, 1H), 8.33 (d, J=2.4,1H), 7.93 (s, 1H), 7.79 (d, J=8.7, 1H), 7.36 (d, J=8.7, 1H), 7.28 (s,1H), 7.25 (d, J=8.4, 1H), 7.20 (d, J=9.6, 1H), 7.07 (s, 2H), 6.25 (s,2H), 2.11 (s, 3H); LCMS: purity: 94.01%; MS (m/e): 424.23 (M+H).

I-296:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.30 (s, 1H), 8.41 (s, 1H), 7.90 (s, 1H), 7.58(d, 2H), 7.24 (s, 1H), 7.18 (m, 2H), 6.62 (s, 1H), 3.64 (s, 3H), 2.09(s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −77.41; LCMS: purity: 95.05%; MS(m/e): 432.21 (M+H).

I-297:N2-(4-methoxy-3-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.15 (br, 1H), 9.04 (s, 1H), 8.33 (s, 1H),7.90 (s, 1H), 7.85 (s, 1H), 7.81 (d, J=8.7, 1H), 7.28 (s, 1H), 7.27 (d,J=6.3, 1H), 7.17 (d, J=9.0, 1H), 7.03 (d, J=9.0, 1H), 3.78 (s, 3H), 2.08(s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −76.81; LCMS: purity: 96.38%; MS(m/e): 432.19 (M+H).

I-298:N2-{4-methoxy-3-[(pyridin-4-yl)methoxy]}phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.51 (br, 1H), 8.76 (s, 1H), 8.52 (d, J=6.0,2H), 8.27 (s, 1H), 7.82 (s, 1H), 7.43 (s, 1H), 7.33 (d, J=8.4, 1H), 7.32(s, 1H), 7.28 (d, J=5.1, 2H), 7.16 (m, 2H), 6.78 (d, J=8.7, 1H), 4.81(s, 2H), 3.71 (s, 3H), 2.07 (s, 3H); LCMS: purity: 93.03%; MS (m/e):471.25 (M+H).

I-299:N2-{4-methoxy-3-[(pyridin-3-yl)methoxy]}phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.81 (br, 1H), 8.51 (s, 1H),8.50 (d, J=7.2, 1H), 7.83 (s, 1H), 7.72 (d, J=7.5, 1H), 7.46 (s, 1H),7.38 (d, J=3.9, 1H), 7.32 (s, 2H), 7.16 (d, J=8.7, 2H), 6.77 (d, J=8.7,1H), 4.80 (s, 2H), 3.68 (s, 3H), 2.07 (s, 3H); LCMS: purity: 91.60%; MS(m/e): 471.23 (M+H).

I-300:N2-{4-methoxy-3-[2-(dimethylamino)ethoxy]}phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.72 (s, 1H), 8.25 (s, 1H), 7.82 (s, 1H), 7.33(s, 2H), 7.31 (d, J=10.2, 1H), 7.16 (d, J=8.7, 1H), 7.13 (d, J=11.1,1H), 6.72 (d, J=9.0, 1H), 3.74 (t, J=5.7, 2H), 3.66 (s, 3H), 2.16 (s,6H), 2.07 (s, 3H); LCMS: purity: 98.92%; MS (m/e): 451.26 (M+H).

I-301:N2-[3,5-bis(trifluoromethyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 10.04 (br, 1H), 8.99 (br, 1H),8.18 (s, 2H), 7.96 (s, 1H), 7.48 (s, 1H), 7.20 (m, 3H), 2.14 (s, 3H);¹⁹F NMR (282 MHz, DMSO) δ −77.91; LCMS: purity: 96.63%; MS (m/e): 470.18(M+H).

I-302:N2-(3,5-dimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.79 (br, 1H), 9.59 (br, 1H),7.83 (s, 1H), 7.30 (d, J=9.6, 1H), 7.20 (s, 2H), 6.98 (s, 2H), 6.65 (s,1H), 2.14 (s, 3H), 2.05 (s, 6H); LCMS: purity: 96.82%; MS (m/e): 362.17(M+H).

I-303:N2-(4-cyano-3-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.55 (br, 1H), 9.98 (s, 1H), 8.56 (s, 1H),8.27 (s, 1H), 8.03 (d, J=8.1, 1H), 7.97 (s, 1H), 7.84 (d, J=9.3, 1H),7.26 (s, 1H), 7.23 (s, 2H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−77.44; LCMS: purity: 93.84%; MS (m/e): 427.16 (M+H).

I-304:N2-[3-(1-hydroxy-2,2,2-trifluoroethyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 10.00 (br, 1H), 9.49 (br, 1H),7.85 (s, 1H), 7.56 (d, J=8.1, 1H), 7.41 (s, 1H), 7.29-7.12 (m, 4H), 6.81(s, 1H), 4.92 (q, 1H), 2.14 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −92.60(d, J=6); LCMS: purity: 96.71%; MS (m/e): 432.14 (M+H).

I-305:N2-(3-methoxycarbonylmethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 8.98 (s, 1H), 8.33 (s, 1H), 7.86(s, 1H), 7.35 (s, 1H), 7.31 (s, 2H), 7.22 (s, 1H), 7.20 (d, J=4.8, 1H),6.99 (t, J=8.1, 1H), 6.35 (d, J=8.1, 1H), 4.56 (s, 2H), 3.67 (s, 3H),2.09 (s, 3H); LCMS: purity: 90.78%; MS (m/e): 422.18 (M+H).

I-306:5-methyl-N2-(3-methylaminocarbonylmethoxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.63 (br, 1H), 8.99 (s, 1H), 8.30 (s, 1H),7.89 (d, 1H), 7.86 (s, 1H), 7.39 (s, 1H), 7.33 (d, 2H), 7.24 (d, J=8.1,1H), 7.18 (d, J=9.0, 1H), 7.01 (t, J=8.1, 1H), 6.38 (d, J=8.1, 1H), 4.26(s, 2H), 2.63 (d, J=4.5, 3H), 2.09 (s, 3H); LCMS: purity: 95.80%; MS(m/e): 421.21 (M+H).

I-307:N2-(4-aminocarbonylmethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (br, 1H), 8.79 (s, 1H), 8.26 (s, 1H),7.81 (s, 1H), 7.52 (d, J=8.7, 2H), 7.45 (s, 1H), 7.35 (d, 2H), 7.31 (s,1H), 7.20 (d, J=8.4, 1H), 6.75 (d, J=8.7, 2H), 4.31 (s, 2H), 2.07 (s,3H); LCMS: purity: 90.97%; MS (m/e): 407.20 (M+H).

I-308:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(4-phenylcarbonylamino)phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 8.94 (s, 1H), 8.30 (s, 1H), 7.90(d, J=7.2, 2H), 7.85 (s, 1H), 7.60 (d, J=9.0, 2H), 7.51 (m, 6H), 7.36(d, J=8.4, 1H), 7.31 (s, 1H), 7.20 (d, J=8.1, 1H), 2.09 (s, 3H); LCMS:purity: 98.33%; MS (m/e): 453.21 (M+H).

I-309:N2-[4-(N-acetyl-N-methyl)amino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.93 (br, 1H), 9.11 (s, 1H), 8.34 (s, 1H),7.86 (s, 1H), 7.67 (d, J=8.4, 2H), 7.29 (d, 2H), 7.22 (d, J=8.1, 1H),7.04 (d, J=8.7, 2H), 3.07 (s, 3H), 2.09 (s, 3H), 1.72 (s, 3H); LCMS:purity: 95.99%; MS (m/e): 405.22 (M+H).

I-310:N2-[3-cyano-4-(pyrrolidin-1-yl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.12 (br, 1H), 8.86 (s, 1H), 8.30 (s, 1H),7.83 (d, J=6.0, 2H), 7.52 (d, J=9.0, 1H), 7.25 (s, 1H), 7.18 (t, J=8.4,2H), 6.64 (d, J=9.3, 1H), 3.40 (t, 4H), 2.07 (s, 3H), 1.90 (t, 4H);LCMS: purity: 96.09%; MS (m/e): 428.20 (M+H).

I-311:N2-(4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.48 (br, 1H), 9.04 (s, 1H), 8.32 (s, 1H),7.85 (s, 1H), 7.65 (d, J=9.3, 2H), 7.28 (d, 2H), 7.20 (d, J=9.3, 1H),7.02 (t, J=75, 1H), 6.93 (d, J=9.0, 2H), 2.08 (s, 3H); ¹⁹F NMR (282 MHz,DMSO) δ −96.76 (d, J=73); LCMS: purity: 97.82%; MS (m/e): 400.16 (M+H).

I-312:N2-(3-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.54 (br, 1H), 9.18 (s, 1H), 8.36 (s, 1H),7.88 (s, 1H), 7.61 (s, 1H), 7.43 (d, J=8.1, 1H), 7.27 (d, 2H), 7.18 (d,J=8.7, 1H), 7.12 (t, J=8.4, 1H), 6.99 (t, J=75, 1H), 6.58 (d, J=9.0,1H), 2.09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −96.98 (d, J=73); LCMS:purity: 97.94%; MS (m/e): 400.16 (M+H).

I-313:N2-(4-difluoromethoxy-3-ethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.02 (s, 1H), 8.35 (s, 1H), 7.87 (s, 1H), 7.51(s, 1H), 7.28 (d, J=7.2, 2H), 7.21 (s, 1H), 7.16 (d, J=8.7, 1H), 6.90(d, J=9.0, 1H), 6.83 (t, J=75, 1H), 3.65 (q, J=6.6, 2H), 2.08 (s, 3H),1.18 (t, J=6.9, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −96.43 (d, J=76); LCMS:purity: 96.55%; MS (m/e): 444.16 (M+H).

I-314:N2-(3-chloro-4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.27 (s, 1H), 8.44 (s, 1H), 7.98 (d, J=2.4,1H), 7.88 (s, 1H), 7.43 (d, J=9.0, 1H), 7.23 (s, 3H), 7.11 (d, J=9.0,1H), 7.03 (t, J=72, 1H), 2.09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −97.27(d, J=73); LCMS: purity: 97.47%; MS (m/e): 434.12 (M+H).

I-315:N2-[3-(cyclopropylaminocarbonylmethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 9.82 (br, 1H), 9.48 (br, 1H),8.04 (d, J=4.2, 1H), 7.84 (s, 1H), 7.25 (s, 3H), 7.09 (d, J=7.5, 1H),7.05 (s, 2H), 6.56 (d, J=9.0, 1H), 4.28 (s, 2H), 2.65 (p, J=3.0, 1H),2.14 (s, 3H), 0.62 (q, J=4.8, 2H), 0.46 (q, J=2.7, 2H); LCMS: purity:91.36%; MS (m/e): 447.23 (M+H).

I-316:N2-[3-aminocarbonyl-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.97 (s, 2H), 8.25 (s, 1H), 7.91 (s, 1H), 7.83(t, J=6.0, 2H), 7.45 (s, 1H), 7.36 (d, J=8.4, 1H), 7.32 (s, 1H), 7.16(d, J=8.1, 1H), 7.03 (d, J=8.4, 1H), 2.84 (t, 4H), 2.22 (s, 3H), 2.08(s, 3H); LCMS: purity: 92.35%; MS (m/e): 475.28 (M+H).

I-317:N2-[4-(isopropoxycarbonylmethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.86 (br, 1H), 9.58 (br, 1H),7.78 (s, 1H), 7.29-7.21 (m, 5H), 6.83 (d, J=8.7, 2H), 4.97 (p, J=6.9,1H), 4.68 (s, 2H), 2.12 (s, 3H), 1.19 (d, J=6.0, 6H); LCMS: purity:76.08%; MS (m/e): 450.24 (M+H).

I-318:N2-[4-(ethylaminocarbonylamino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.78 (br, 1H), 9.54 (br, 1H),8.40 (s, 1H), 7.76 (s, 1H), 7.26 (s, 7H), 6.07 (s, 1H), 3.07 (q, J=6.6,2H), 2.12 (s, 3H), 1.02 (t, J=6.9, 3H); LCMS: purity: 94.25%; MS (m/e):420.24 (M+H).

I-319:N2-[3-(aminocarbonylmethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 7.84 (s, 1H), 7.42 (s, 1H), 7.37(s, 1H), 7.27 (s, 3H), 7.10 (m 3H), 6.61 (s, 1H), 4.29 (s, 2H), 2.13 (s,3H); LCMS: purity: 91.03%; MS (m/e): 407.19 (M+H).

I-320:5-methyl-N2-[3-(morpholinocarbonylmethoxy)]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.95 (br, 1H), 9.58 (br, 1H),7.85 (s, 1H), 7.30 (d, J=8.7, 1H), 7.23 (d, J=6.6, 2H), 7.11 (t, J=7.8,1H), 6.99 (d, J=9.6, 2H), 6.61 (d, J=7.2, 1H), 4.69 (s, 2H), 3.55 (s,4H), 3.41 (s, 4H), 2.14 (s, 3H); LCMS: purity: 96.33%; MS (m/e): 477.25(M+H).

I-321:5-methyl-N2-[3-(4-methylpiperazin-1-yl)carbonyl]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.15 (br, 1H), 9.88 (br, 1H),9.43 (br, 1H), 7.92 (s, 1H), 7.58 (d, J=7.8, 1H), 7.52 (s, 1H),7.30-7.22 (m, 4H), 7.06 (d, J=7.2, 1H), 3.40 (br, 4H), 3.03 (br, 4H),2.80 (s, 3H), 2.13 (s, 3H); LCMS: purity: 95.46%; MS (m/e): 460.29(M+H).

I-322:5-methyl-N2-[4-(4-methylpiperazin-1-yl)carbonyl]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.83 (br, 1H), 7.93 (s, 1H),7.61 (d, J=9.0, 2H), 7.30 (m, 5H), 3.39 (m, 2H), 3.23 (m, 2H), 3.06 (m,2H), 2.81 (s, 3H), 2.13 (s, 3H); LCMS: purity: 86.87%; MS (m/e): 460.30(M+H).

I-323:5-methyl-N2-[3-methylaminocarbonyl-4-(4-methylpiperazino)]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.02 (br, 1H), 9.64 (br, 2H),8.45 (d, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.48 (d, 1H), 7.21 (s, 3H),7.03 (d, J=8.4, 1H), 3.49 (d, J=9.3, 2H), 3.17 (t, J=6.6, 4H), 2.94 (d,2H), 2.87 (s, 3H), 2.81 (d, J=4.8, 3H), 2.13 (s, 3H); LCMS: purity:93.72%; MS (m/e): 489.30 (M+H).

I-324:N2-[4-(1-aminocarbonyl-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.83 (s, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 7.49(d, J=9.0, 2H), 7.46 (s, 1H), 7.34 (d, J=9.6, 1H), 7.29 (s, 1H), 7.18(d, J=8.7, 2H), 6.72 (d, J=9.0, 2H), 2.06 (s, 3H), 1.32 (s, 6H); LCMS:purity: 94.37%; MS (m/e): 435.21 (M+H).

I-325:5-methyl-N2-(2-methyl-3-methylaminocarbonylmethoxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.15 (s, 1H), 8.06 (s, 1H), 7.83 (br, 1H), 7.76(s, 1H), 7.39 (d, J=9.3, 1H), 7.29 (s, 1H), 7.16 (d, J=7.5, 1H), 7.04(d, J=8.1, 2H), 6.58 (d, J=8.4, 1H), 4.42 (s, 2H), 2.65 (d, J=4.5, 3H),2.07 (s, 3H), 2.04 (s, 3H); LCMS: purity: 94.87%; MS (m/e): 435.26(M+H).

I-326:N2-(3-dimethylaminocarbonylmethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.30 (br, 1H), 8.94 (s, 1H), 8.31 (s, 1H),7.87 (s, 1H), 7.34 (d, J=6.6, 3H), 7.21 (d, J=9.0, 2H), 6.99 (t, J=8.1,1H), 6.37 (d, J=8.4, 1H), 4.60 (s, 2H), 2.94 (s, 3H), 2.82 (s, 3H), 2.08(s, 3H); LCMS: purity: 93.47%; MS (m/e): 435.22 (M+H).

I-327:N2-(3-cyano-4-morpholino)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.44 (br, 1H), 9.20 (s, 1H), 8.41 (s, 1H),8.12 (d, J=2.4, 1H), 7.88 (s, 1H), 7.65 (d, J=7.5, 1H), 7.24 (d, J=8.1,3H), 7.02 (d, J=9.0, 1H), 3.71 (t, 4H), 2.97 (t, 4H), 2.08 (s, 3H);LCMS: purity: 93.52%; MS (m/e): 444.22 (M+H).

I-328:N2-(3-methoxy-2-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.70 (s, 1H), 9.55 (s, 1H), 7.71(s, 1H), 7.22 (m, 3H), 7.16 (d, J=8.1, 1H), 6.92 (t, J=6.9, 2H), 3.78(s, 3H), 2.11 (s, 3H), 1.96 (s, 3H); LCMS: purity: 94.95%; MS (m/e):378.22 (M+H).

I-329: N2-[3-chloro-4-(pyridin-4-yl)]phenyl5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 9.55 (d, J=7.8, 2H), 9.38 (s,1H), 8.41 (s, 1H), 8.30 (d, J=7.2, 2H), 7.51 (d, J=8.7, 1H), 7.40 (s,1H), 7.34 (s, 2H), 6.81 (s, 1H), 6.73 (d, 1H), 6.50 (br, 1H), 2.31 (s,3H); LCMS: purity: 68.83%; MS (m/e): 445.19 (M+H).

I-330:5-methyl-N-4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[4-(pyridin-4-yl)-3-trifluoromethyl]phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.65 (d, J=7.2, 2H), 9.40 (s,1H), 8.42 (s, 1H), 8.13 (d, J=7.2, 2H), 7.39 (s, 1H), 7.34 (m, 3H), 7.11(s, 1H), 6.93 (d, J=8.1, 1H), 6.43 (br, 1H), 2.32 (s, 3H); ¹⁹F NMR (282MHz, DMSO) δ −70.12; LCMS: purity: 86.84%; MS (m/e): 479.21 (M+H).

I-331:N2-[3-hydroxymethyl-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.70 (br, 1H), 9.52 (br, 1H), 7.82 (s, 1H),7.37 (br, 2H), 7.25 (s, 3H), 6.94 (d, 1H), 4.45 (s, 2H), 3.49 (br, 4H),3.14 (s, 3H), 2.86 (s, 4H), 2.12 (s, 3H); LCMS: purity: 73.83%; MS(m/e): 462.30 (M+H).

I-332:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(4-piperazino)phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 9.99 (br, 1H), 9.64 (br, 1H),8.70 (br, 2H), 7.81 (s, 1H), 7.29-7.22 (m, 5H), 6.90 (d, J=8.7, 2H),3.24 (t, 8H), 2.12 (s, 3H); LCMS: purity: 94.64%; MS (m/e): 418.24(M+H).

I-333:N2-[4-(4-ethylaminocarbonyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 9.88 (s, 1H), 9.69 (s, 1H), 7.74(s, 1H), 7.30-7.16 (m, 5H), 6.89 (d, J=7.8, 2H), 6.57 (s, 1H), 3.39 (t,4H), 3.02 (t, 6H), 2.12 (s, 3H), 1.00 (t, J=7.2, 3H); LCMS: purity:73.76%; MS (m/e): 489.28 (M+H).

I-334:N2-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.08 (s, 1H), 9.66 (s, 1H),7.85 (s, 1H), 7.38 (d, J=8.7, 2H), 7.28 (d, J=8.7, 1H), 7.21 (s, 2H),7.03 (d, J=9.0, 2H), 2.13 (s, 3H), 1.63 (s, 6H); LCMS: purity: 97.92%;MS (m/e): 417.24 (M+H).

I-335:N2-[3-(1-aminocarbonyl-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 9.97 (s, 1H), 9.54 (s, 1H), 7.86(s, 1H), 7.38 (s, 1H), 7.30 (d, J=9.6, 1H), 7.24 (d, J=8.4, 3H), 7.09(d, J=4.5, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 2.13 (s, 3H), 1.35 (s, 6H);LCMS: purity: 97.33%; MS (m/e): 435.25 (M+H).

I-336:N2-(3-methoxy-4-methoxycarbonyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.36 (s, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.51(d, J=8.4, 1H), 7.48 (s, 1H), 7.36 (d, J=6.6, 1H), 7.30 (d, 2H), 7.21(d, J=9.3, 1H), 3.68 (s, 3H), 3.52 (s, 3H), 2.10 (s, 3H); LCMS: purity:85.55%; MS (m/e): 422.23 (M+H).

I-337:N2-(3-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.55 (s, 1H), 8.94 (s, 1H), 8.33 (s, 1H), 7.86(s, 1H), 7.31 (t, J=6.9, 3H), 7.18 (t, J=8.1, 2H), 7.00 (t, J=8.1, 1H),6.38 (d, J=7.8, 1H), 3.57 (s, 3H), 2.08 (s, 3H); LCMS: purity: 94.08%;MS (m/e): 364.22 (M+H).

I-338:5-methyl-N2-(4-morpholino)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.68 (s, 1H), 7.74 (s, 1H),7.27-7.16 (m, 5H), 6.88 (d, 2H), 3.71 (t, 4H), 3.04 (t, 4H), 2.12 (s,3H); LCMS: purity: 73.88%; MS (m/e): 419.18 (M+H).

I-339:N2-(3-cyano-4-thiomorpholino)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.34 (br, 1H), 9.20 (s, 1H), 8.41 (s, 1H),8.11 (s, 1H), 7.88 (s, 1H), 7.65 (d, J=9.6, 1H), 7.23 (d, J=6.3, 3H),7.03 (d, J=9.0, 1H), 3.20 (t, 4H), 2.74 (t, 4H), 2.08 (s, 3H); LCMS:purity: 84.84%; MS (m/e): 460.24 (M+H).

I-340:N2-[3-methoxy-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.12 (s, 1H), 9.66 (s, 2H),7.83 (s, 1H), 7.26 (d, J=9.3, 1H), 7.22 (d, 2H), 6.94 (d, J=9.6, 2H),6.82 (d, J=8.4, 1H), 3.50 (s, 3H), 3.45 (br, 4H), 3.18 (q, 2H), 2.85 (t,5H), 2.13 (s, 3H); LCMS: purity: 92.71%; MS (m/e): 462.25 (M+H).

I-341:N2-[3-cyano-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.18 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.87(s, 1H), 7.63 (d, J=9.3, 1H), 7.23 (d, J=8.7, 3H), 6.99 (d, J=9.0, 1H),2.98 (t, 4H), 2.21 (s, 3H), 2.07 (s, 3H); LCMS: purity: 91.59%; MS(m/e): 457.27 (M+H).

I-342:N2-[3-(1-cyano-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.98 (s, 1H), 9.48 (s, 1H), 7.88(s, 1H), 7.31-7.18 (m, 6H), 6.83 (d, J=7.8, 1H), 2.13 (s, 3H), 1.57 (s,6H); LCMS: purity: 97.74%; MS (m/e): 417.27 (M+H).

I-343:N2-[4-(4-acetyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.73 (s, 1H), 8.25 (s, 1H), 7.81 (s, 1H), 7.48(d, J=8.4, 2H), 7.33 (d, J=8.1, 1H), 7.30 (s, 1H), 7.20 (d, J=8.1, 1H),6.76 (d, J=8.7, 2H), 3.54 (s, 4H), 2.99 (t, 2H), 2.92 (t, 2H), 2.05 (s,3H), 2.01 (s, 3H); LCMS: purity: 94.65%; MS (m/e): 460.28 (M+H).

I-344:N2-[4-(4-ethoxycarbonyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.01 (br, 1H), 8.71 (s, 1H), 8.24 (s, 1H),7.80 (s, 1H), 7.47 (d, J=8.7, 2H), 7.32 (d, J=11.1, 2H), 7.19 (d, J=8.7,1H), 6.75 (d, J=8.7, 2H), 4.03 (q, J=6.9, 2H), 3.46 (t, 4H), 2.94 (t,J=4.5, 4H), 2.05 (s, 3H), 1.17 (t, J=7.2, 3H); LCMS: purity: 91.97%; MS(m/e): 490.26 (M+H).

I-345:N2-[3-(4-acetyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 10.04 (s, 1H), 9.71 (s, 1H),7.82 (s, 1H), 7.27 (d, J=9.3, 1H), 7.22 (d, J=6.6, 2H), 7.11 (t, J=8.1,1H), 6.89 (s, 1H), 6.83 (d, J=8.1, 1H), 6.74 (d, J=8.1, 1H), 3.45 (t,4H), 2.97 (t, 2H), 2.84 (t, 2H), 2.14 (s, 3H), 2.01 (s, 3H); LCMS:purity: 100%; MS (m/e): 460.08 (M+H).

I-346:N2-[3-(4-ethoxycarbonyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 9.85 (br, 1H), 9.52 (br, 1H),7.81 (s, 1H), 7.24 (s, 3H), 7.09 (t, J=8.1, 1H), 6.93 (s, 1H), 6.86 (d,J=7.5, 1H), 6.69 (d, J=6.9, 1H), 4.04 (d, J=7.2, 2H), 3.38 (s, 4H), 2.90(s, 4H), 2.12 (s, 3H), 1.18 (t, J=6.9, 3H); LCMS: purity: 93.55%; MS(m/e): 490.32 (M+H).

I-347:N2-(4-difluoromethoxy-3-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.63 (s, 1H), 9.61 (s, 1H), 8.89 (br, 1H),7.88 (s, 1H), 7.75 (d, J=14.4, 1H), 7.29-7.10 (m, 5H), 7.05 (t, J=74,1H), 2.10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −97.45 (d, J=73); LCMS:purity: 98.63%; MS (m/e): 418.21 (M+H).

I-348:N2-(3,5-dichloro-4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 9.48 (s, 1H), 8.55 (s, 1H), 7.91(s, 1H), 7.77 (s, 2H), 7.25 (d, J=8.1, 1H), 7.20 (s, 1H), 7.16 (d,J=8.1, 1H), 6.96 (t, J=73, 1H), 2.08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−95.79 (d, J=73); LCMS: purity: 93.57%; MS (m/e): 468.13 (M+H).

I-349:N2-(4-fluoro-3-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.34 (br, 1H), 8.96 (s, 1H), 8.33 (s, 1H),7.87 (s, 1H), 7.46 (d, J=8.1, 1H), 7.31 (d, J=5.4, 2H), 7.23 (d, J=8.7,1H), 7.20 (d, J=9.3, 1H), 6.93 (t, J=9.9, 1H), 3.55 (s, 3H), 2.07 (s,3H); ¹⁹F NMR (282 MHz, DMSO) δ −160.84; LCMS: purity: 100%; MS (m/e):382.03 (M+H).

I-350:N2-(3-fluoro-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 9.47 (br, 1H), 9.05 (br, 1H),7.83 (s, 1H), 7.52 (d, J=14.7, 1H), 7.24 (s, 3H), 7.10 (d, 1H), 6.99 (t,J=9.3, 1H), 3.74 (s, 3H), 2.10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−149.86; LCMS: purity: 100%; MS (m/e): 382.02 (M+H).

I-351:N2-(3-methoxy-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 7.86(s, 1H), 7.35 (d, J=10.5, 2H), 7.25 (s, 1H), 7.20 (t, J=6.9, 2H), 6.84(d, J=8.4, 1H), 3.50 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H); LCMS: purity:90.74%; MS (m/e): 378.26 (M+H).

I-352:N2-(3-fluoro-5-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 9.15 (s, 1H), 8.42 (s, 1H), 7.88(s, 1H), 7.26 (s, 1H), 7.20 (d, J=8.1, 3H), 6.99 (s, 1H), 6.22 (d,J=10.8, 1H), 3.60 (s, 3H), 2.08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−127.86; LCMS: purity: 96.96%; MS (m/e): 382.20 (M+H).

I-353:N2-(3-difluoromethoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.97 (br, 1H), 9.10 (br, 1H),7.94 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.20 (m, 3H), 7.19 (t, J=73,1H), 7.01 (s, 1H), 2.13 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −77.31; LCMS:purity: 95.73%; MS (m/e): 468.21 (M+H).

I-354:N2-(3-methoxy-4-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 9.88 (br, 1H), 9.06 (br, 1H),7.92 (s, 1H), 7.35 (d, J=9.0, 2H), 7.28 (d, 4H), 3.57 (s, 3H), 2.13 (s,3H); ¹⁹F NMR (282 MHz, DMSO) δ −75.24; LCMS: purity: 86.29%; MS (m/e):432.23 (M+H).

I-355:N2-(3,5-di-tert-butyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.86 (s, 1H), 9.50 (s, 1H), 7.82(s, 1H), 7.24-7.17 (m, 5H), 7.09 (s, 1H), 2.13 (s, 3H), 1.10 (s, 18H);LCMS: purity: 98.22%; MS (m/e): 446.35 (M+H).

I-356:N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.37 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 7.96(s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.32 (s, 2H), 6.68 (s, 1H), 5.62(d, J=10.8, 2H), 3.71 (s, 3H), 2.12 (s, 3H), 1.30 (s, 18H); ¹⁹F NMR (282MHz, DMSO) δ −76.83; ³¹P NMR (121 MHz, DMSO) δ −10.51; LCMS: purity:95.06%; MS (m/e): 598.30.

I-357:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N-4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 7.95 (s, 1H), 7.67 (s, 1H), 7.29 (s, 2H), 6.66(s, 1H), 5.56 (d, 2H), 3.74 (s, 3H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz,DMSO) δ −76.80; LCMS: purity: 81.15%; MS (m/e): 542.16 (M+H).

I-358:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N-4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediaminebis-sodium salt

¹H NMR (300 MHz, DMSO) δ 7.92 (s, 1H), 7.53 (br, 3H), 7.18 (s, 2H), 6.59(br, 2H), 5.44 (d, 2H), 3.79 (s, 3H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz,DMSO) δ −76.53; LCMS: purity: 93.44%; MS (m/e): 542.20 (M+H).

I-359:N2-(3,5-difluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 9.61 (s, 1H), 8.78 (s, 1H), 7.91(s, 1H), 7.30-7.15 (m, 5H), 6.59 (t, J=9.0, 1H), 2.10 (s, 3H); ¹⁹F NMR(282 MHz, DMSO) δ −126.14; LCMS: purity: 96.57%; MS (m/e): 370.20 (M+H).

I-360:N2-(3-fluoro-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.55 (s, 1H), 9.61 (s, 1H), 8.53 (s, 1H), 7.92(d, J=11.1, 2H), 7.69 (s, 1H), 7.22 (m, 3H), 6.96 (d, J=8.7, 1H), 2.10(s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −77.18, −125.92; LCMS: purity:94.90%; MS (m/e): 420.22 (M+H).

I-361:N2-(4-fluoro-3-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 9.35 (s, 1H), 8.42 (s, 1H), 8.08(d, J=5.7, 1H), 7.90 (s, 1H), 7.85 (d, 1H), 7.30-7.19 (m, 4H), 2.08 (s,3H); ¹⁹F NMR (282 MHz, DMSO) δ −75.89, −142.78; LCMS: purity: 97.69%; MS(m/e): 420.21 (M+H).

I-362:N2-(4-fluoro-3-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.13 (br, 1H), 8.94 (s, 1H), 8.33 (s, 1H),7.85 (s, 1H), 7.55 (d, J=7.2, 1H), 7.35 (dd, J=9.9, 5.4, 1H), 7.28 (m,2H), 7.22 (d, J=9.0, 1H), 6.88 (t, J=9.3, 1H), 2.07 (s, 3H), 1.99 (s,3H); ¹⁹F NMR (282 MHz, DMSO) δ −143.48; LCMS: purity: 97.37%; MS (m/e):366.22 (M+H).

I-363:N2-(3-fluoro-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.11 (s, 1H), 8.39 (s, 1H), 7.87(s, 1H), 7.62 (d, J=13.5, 1H), 7.28-7.15 (m, 4H), 6.98 (t, J=8.4, 1H),2.08 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ −132.82; LCMS: purity: 98.10%;MS (m/e): 366.22 (M+H).

I-364:N2-(3-chloro-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.33 (br, 1H), 9.10 (s, 1H), 8.39 (s, 1H),7.86 (d, J=5.7, 2H), 7.32 (d, J=8.1, 1H), 7.23 (d, 3H), 7.05 (d, J=8.4,1H), 2.17 (s, 3H), 2.07 (s, 3H); LCMS: purity: 96.65%; MS (m/e): 382.20(M+H).

I-365:N2-(3,4,5-trimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.39 (br, 1H), 8.70 (s, 1H), 8.29 (s, 1H),7.83 (s, 1H), 7.30 (d, J=6.3, 2H), 7.21 (m, 3H), 2.06 (s, 3H), 1.99 (s,6H), 1.98 (s, 3H); LCMS: purity: 96.73%; MS (m/e): 376.27 (M+H).

I-366:N2-(3-chloro-4-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.28%; MS (m/e): 452.19 (M+H).

I-367:N2-(4-trifluoromethylthio)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 95.52%; MS (m/e): 434.16 (M+H).

I-368:N2-(3-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 95.77%; MS (m/e): 352.20 (M+H).

I-369:N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.05%; MS (m/e): 392.28 (M+H).

I-370:N2-(3-carboxamide-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 95.87%; MS (m/e): 445.24 (M+H).

I-371:N2-(3,5-diisopropyl-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 98.88%; MS (m/e): 448.33 (M+H).

I-372:N2-(3-isopropoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 460.14 (M+H).

I-373:N2-(3-cyano-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 94.66%; MS (m/e): 389.23 (M+H).

I-374:N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.43 (br, 1H), 8.85 (s, 1H), 8.33 (s, 1H),7.84 (s, 1H), 7.28 (d, J=6.6, 4H), 7.21 (d, J=9.0, 1H), 2.06 (s, 3H),1.98 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ −147.89; LCMS: purity: 97.65%;MS (m/e): 380.24 (M+H).

I-375:N2-(4-fluoro-3-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.82%; MS (m/e): 436.21 (M+H).

I-376:N2-(3-fluoro-4-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.88%; MS (m/e): 436.21 (M+H).

I-377:N2-(4-chloro-3-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 95.28%; MS (m/e): 452.14 (M+H).

I-378:N2-(3-chloro-5-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 95.29%; MS (m/e): 452.19 (M+H).

I-379:5-methyl-N2-(3-methyl-5-trifluoromethoxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.81%; MS (m/e): 432.24 (M+H).

I-380:N2-(4-cyano-3-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.08%; MS (m/e): 389.07 (M+H).

I-381:N2-(3,5-difluoro-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 400.04 (M+H).

I-382:5-methyl-N2-(4-morpholinomethyl)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 85.62%; MS (m/e): 433.28 (M+H).

I-383:N2-(4-chloro-3-cyano-5-ethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 90.90%; MS (m/e): 421.24 (M+H).

I-384:N2-[3-(2-methoxy)ethoxy-5-trifluoromethyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 86.68%; MS (m/e): 476.27 (M+H).

I-385:N2-(4-difluoromethoxy-3,5-dimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.79%; MS (m/e): 428.26 (M+H).

I-386:N2-[3-(1-aminocarbonyl-1-methyl)ethoxy-4-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 98.11%; MS (m/e): 453.04 (M+H).

I-387:N2-(4-difluoromethoxy-3-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 414.08 (M+H).

I-388:N2-(3,5-difluoro-4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 93.98%; MS (m/e): 436.22 (M+H).

I-389:N2-[4-(1-aminocarbonyl-1-methyl)ethoxy-3,5-dimethyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 91.03%; MS (m/e): 463.34 (M+H).

I-390:N2-(3-difluoromethoxy-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 93.39%; MS (m/e): 414.25 (M+H).

I-391:N2-[4-(1-aminocarbonyl-1-methyl)ethoxy-3-methyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 449.14 (M+H).

I-392:N2-[3-(1-aminocarbonyl-1-methyl)ethoxy-4-methyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 98.47%; MS (m/e): 449.11 (M+H).

I-393:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminebesylate salt

LCMS: purity: 94.20%; MS (m/e): 432.23 (M+H).

I-394:N2-(4-chloro-3,5-dimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.66%; MS (m/e): 396.14 (M+H).

I-395:N2-[4-(1-aminocarbonyl-1-methyl)ethoxy-3,5-difluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 471.08 (M+H).

I-396:N2-[3-(1-methoxy-2,2,2-trifluoroethyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 446.10 (M+H).

I-397:N2-[3-(1-cyano-1-methyl)ethoxy-4-methyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 431.15 (M+H).

I-398:N2-(3,4-difluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.76%; MS (m/e): 370.08 (M+H).

I-399:N2-(3-chloro-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 386.04 (M+H).

I-400:N2-(4-chloro-3-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 98.43%; MS (m/e): 386.07 (M+H).

I-401:N2-(3-difluoromethoxy-5-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 92.54%; MS (m/e): 418.18 (M+H).

I-402:N2-[3-(1-aminocarbonyl-1-methyl)ethoxy-5-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.74%; MS (m/e): 453.23 (M+H).

I-403:5-(5-Methyl-2-m-tolylamino-pyrimidin-4-ylamino)-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.77 (s, 1H), 10.01 (s, 1H), 9.63 (s, 1H),7.86 (s, 2H), 7.21 (m, 5H), 6.84 (d, J 6.8, 1H), 2.13 (s, 3H), 2.05 (s,3H) ppm; MS (ES) 348 (M+H);

I-404:5-{2-[4-(3-Dimethylamino-propoxy)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.78 (s, 1H), 10.78 (s, 1H), 9.83 (s, 2H),7.93 (s, 1H), 7.61 (s, 1H), 7.55 (d, J=11.1, 1H), 7.19 (m, 3H), 4.11 (t,J=5.8, 2H), 3.15 (m, 2H), 2.80 (s, 6H), 2.13 (m, 5H) ppm; MS (ES) 503(M+H);

I-405:N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3,4,5-trimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.81 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.88(s, 1H), 7.34 (m, 4H), 5.61 (d, J=11.4, 2H), 2.09 (s, 9H), 2.01 (s, 3H),1.32 (s, 18H); ³¹P NMR (121 MHz, DMSO) δ −10.15; LCMS: purity: 98.17%;MS (m/e): 598.43 (M+H).

I-406:5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N-2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine

LCMS: purity: 78.10%; MS (m/e): 486.12 (M+H).

I-407:5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N-2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediaminebis-sodium salt

¹H NMR (300 MHz, DMSO) δ 7.84 (s, 1H), 7.62 (s, 2H), 7.18 (br, 4H), 5.41(d, 2H), 2.14 (s, 6H), 2.09 (s, 3H), 2.02 (s, 3H); LCMS: purity: 93.88%;MS (m/e): 486.02 (M+H).

I-408:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(3,4,5-trifluoro)phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.96 (s, 1H), 9.32 (s, 1H), 7.92(s, 1H), 7.40 (d, J=6.6, 1H), 7.36 (d, J=6.3, 1H), 7.30 (d, J=8.4, 1H),7.21 (s, 1H), 7.14 (d, J=9.0, 1H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO)δ −151.27; LCMS: purity: 99.67%; MS (m/e): 388.15 (MH+).

I-409:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminetosylate salt

¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 10.04 (br, 1H), 9.62 (br, 1H),7.90 (s, 1H), 7.45 (d, J=7.8, 2H), 7.33 (s, 1H), 7.29-7.14 (m, 5H), 7.09(d, J=8.4, 2H), 6.83 (s, 1H), 3.67 (s, 3H), 2.26 (s, 3H), 2.14 (s, 3H);¹⁹F NMR (282 MHz, DMSO) δ −77.21; LCMS: purity: 100%; MS (m/e): 432.09(MH+).

I-410:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminemesylate salt

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 10.13 (s, 1H), 9.70 (br, 1H),7.90 (s, 1H), 7.30 (s, 1H), 7.26 (d, J=8.1, 2H), 7.17 (s, 1H), 7.12 (d,J=8.4, 1H), 6.85 (s, 1H), 3.67 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H); ¹⁹FNMR (282 MHz, DMSO) δ −77.23; LCMS: purity: 95.41%; MS (m/e): 432.17(MH+).

I-411:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminesulfate salt

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 10.13 (s, 1H), 9.74 (s, 1H),7.90 (s, 1H), 7.30-7.24 (m, 3H), 7.16 (s, 1H), 7.12 (d, J=8.1, 1H), 6.86(s, 1H), 3.67 (s, 3H), 2.15 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −77.24;LCMS: purity: 98.00%; MS (m/e): 432.15 (MH+).

I-412:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminehydrogen chloride salt

¹H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 10.36 (br, 1H), 9.70 (br, 1H),7.92 (s, 1H), 7.31-7.24 (m, 3H), 7.17 (s, 1H), 7.12 (d, J=8.7, 1H), 6.84(s, 1H), 3.67 (s, 3H), 2.14 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −77.24;LCMS: purity: 98.03%; MS (m/e): 432.17 (MH+).

I-413:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminesodium salt

¹H NMR (300 MHz, DMSO) δ 9.10 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.73(s, 1H), 7.60 (s, 1H), 6.76 (s, 1H), 6.73 (d, J=7.5, 1H), 6.64 (d,J=7.8, 1H), 6.58 (s, 1H), 3.54 (s, 3H), 2.04 (s, 3H); ¹⁹F NMR (282 MHz,DMSO) δ −76.80; LCMS: purity: 97.89%; MS (m/e): 432.18 (MH+).

I-414:N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminecholine salt

¹H NMR (300 MHz, DMSO) δ 9.10 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.72(s, 1H), 7.60 (s, 1H), 6.76 (s, 1H), 6.73 (d, J=7.8, 1H), 6.64 (d,J=7.8, 1H), 6.58 (s, 1H), 3.81 (q, J=4.5, 2H), 3.54 (s, 3H), 3.36 (t,J=5.1, 2H), 3.07 (s, 9H), 2.04 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−76.80; LCMS: purity: 100%; MS (m/e): 432.28 (MH+).

I-415:N2-(3,5-difluoro-4-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 10.03 (s, 1H), 8.86 (s, 1H),7.96 (s, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.28 (d, J=8.4, 1H), 7.21 (s,1H), 7.16 (d, J=8.4, 1H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−69.54, −128.85; LCMS: purity: 95.67%; MS (m/e): 438.15 (MH+).

I-416:N2-[3-(1-cyano-1-methyl)ethoxy-5-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 10.00 (br, 1H), 9.37 (br, 1H),7.91 (s, 1H), 7.35 (s, 1H), 7.29 (d, J=8.7, 1H), 7.21 (s, 1H), 7.18 (d,J=8.4, 1H), 7.06 (s, 1H), 6.57 (d, J=9.6, 1H), 2.13 (s, 3H), 1.63 (s,6H); ¹⁹F NMR (282 MHz, DMSO) δ −126.51; LCMS: purity: 99.33%; MS (m/e):435.21 (MH+).

I-417:N2-[3-(1-cyano-1-methyl)ethoxy-4-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 7.86 (s, 1H), 7.56 (br, 1H),7.32 (br, 1H), 7.23 (m, 4H), 2.12 (s, 3H), 1.58 (s, 6H); LCMS: purity:96.32%; MS (m/e): 435.23 (MH+).

I-418:N2-(4-chloro-3-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.33 (s, 1H), 8.41 (s, 1H), 7.90(s, 1H), 7.78 (s, 1H), 7.59 (d, J=9.0, 1H), 7.29 (m, 3H), 7.22 (d,J=9.3, 1H), 6.93 (t, J=73, 1H), 2.09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−96.85 (d, J=73); LCMS: purity: 97.12%; MS (m/e): 434.09 (MH+).

I-419:5-(2-(4-isopropylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 10.11 (s, 1H), 9.72 (s, 1H),7.83 (s, 1H), 7.32-7.01 (m, 7H), 2.80 (dt, J=13.6, 7.0, 1H), 2.13 (s,3H), 1.13 (d, J=6.9, 6H); LCMS (m/z): 376 (MH⁺).

I-420:5-(2-(4-tert-butylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.81 (s, 1H), 10.21 (s, 1H), 9.82 (s, 1H),7.84 (s, 1H), 7.29 (d, J=8.6, 1H), 7.23 (br s, 5H), 7.12 (d, J=8.6, 1H),2.13 (s, 3H), 1.21 (s, 9H); LCMS (m/z): 390 (MH⁺).

I-421:5-(2-(p-toluidino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.79 (s, 1H), 10.19 (s, 1H), 9.70 (s, 1H),7.84 (s, 1H), 7.32-7.13 (m, 5H), 7.03 (d, J=8.2, 2H), 2.22 (s, 3H), 2.12(s, 3H); LCMS (m/z): 348 (MH⁺).

I-422:5-(2-(3-(isopropoxymethyl)-4-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 10.03 (s, 1H), 9.60 (s, 1H),7.79 (s, 1H), 7.39-7.11 (m, 5H), 6.88 (d, J=9.0, 1H), 4.32 (s, 2H), 3.74(s, 3H), 3.61-3.50 (m, 2H), 2.12 (s, 3H), 1.07 (d, J=6.1, 6H); LCMS(m/z): 436 (MH⁺).

I-423:5-(2-(3-(1-hydroxyethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₁H₂₁N₅O₄. MS (ESI) m/z 408.12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.90(s, 1H, NH), 8.31 (s, 1H, NH), 8.13 (s, 1H, NH), 7.86 (s, 1H, ArH), 7.30(m, 2H, ArH), 7.25-7.14 (m, 2H, ArH), 7.07 (s, 1H, ArH), 6.40 (s, 1H,ArH), 4.44 (q, J=6.4, 1H, CH), 2.07 (s, 3H, OCH₃), 1.17 (d, J=9.0, 3H,CH₃).

I-424:5-[2-(3-Chloro-4-hydroxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 384 (M+H);

I-425:5-[2-(4-Hydroxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 350 (M+H);

I-426:5-{2-[4-(2-Dimethylamino-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 12.03-11.73 (s, 1H), 10.42-10.23 (s, 1H),9.64-9.42 (s, 1H), 7.88 (s, 1H), 7.36 (d, J=9.0, 1H), 7.25 (d, J=12.2,2H), 6.86 (d, J=9.0, 1H), 4.23 (m, 2H), 3.48 (m, 2H), 2.84 (s, 6H), 2.11(s, 3H) ppm; MS (ES) 368 (M+H);

I-427:5-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 10.15 (s, 1H), 9.46 (s, 1H),7.97 (s, 1H), 7.40 (br s, 2H), 7.07 (s, 1H), 7.05 (s, 1H), 6.86 (s, 1H),3.71 (s, 3H), 2.30 (s, 3H), 2.18 (s, 3H); LRMS (M+) m/z 446.10.

I-428:5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.95 (s, 1H), 9.67 (s, 1H), 7.89(s, 1H), 7.10 (s, 1H), 7.09 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.51(s, 1H), 3.63 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H); LRMS(M+) m/z 392.09.

I-429:5-(2-(4-methoxy-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 9.98 (s, 1H), 9.64 (s, 1H), 7.82(s, 1H), 7.22-7.17 (m, 2H), 7.13 (s, 1H), 7.12 (s, 1H), 6.90 (d, J=8.4,1H), 3.79 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H); LRMS (M+)m/z 392.13.

I-430:7-fluoro-5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 9.95 (s, 1H), 9.55 (s, 1H), 7.94(s, 1H), 7.43 (d, J=12.9, 1H), 7.16 (s, 1H), 6.88 (br s, 2H), 6.52 (s,1H), 3.67 (s, 3H), 2.18 (br s, 6H); LRMS (M+) m/z 396.05.

I-431:7-fluoro-5-(2-(4-methoxy-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.14 (s, 1H), 10.02 (s, 1H), 9.59 (s, 1H),7.87 (s, 1H), 7.48 (d, J=12.1, 1H), 7.23-7.17 (m, 3H), 6.94 (d, J=9.4,1H), 3.81 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H); LRMS (M+) m/z 396.05.

I-432:5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.81 (s, 1H), 10.19 (s, 1H), 9.78 (s, 1H),7.89 (s, 1H), 7.36-7.26 (m, 3H), 6.97 (d, J=6.9, 1H), 6.92 (d, J=5.3,1H), 3.64 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H); LRMS (M+) m/z 396.14.

I-433:5-(2-(4-(difluoromethoxy)-3-(fluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 11.61 (br s, 1H), 9.18 (s, 1H), 8.37 (s, 1H),7.88 (s, 1H), 7.79 (s, 1H), 7.67 (d, J=9.0, 1H), 7.33-7.23 (m, 3H), 7.03(d, J=8.7, 1H), 7.00 (t, J=63.9, 1H), 5.30 (s, 1H), 5.14 (s, 1H), 2.08(s, 3H); LCMS (m/z): 432 (MH⁺).

I-434:N2-(4-cyano-3-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

1H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 9.88 (br, 1H), 9.32 (br, 1H),7.87 (s, 1H), 7.51 (d, 1H), 7.35 (br, 1H), 7.28-7.19 (m, 4H), 6.99 (t,J=73, 1H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −97.46 (d, J=73);LCMS: purity: 97.87%; MS (m/e): 425.19 (MH+).

I-435:N2-(3-difluoromethoxy-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.94 (br, 1H), 8.75 (br, 1H),7.96 (s, 1H), 7.75 (s, 1H), 7.65 (m, 2H), 7.27 (s, 3H), 7.07 (t, J=73,1H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −97.82 (d, J=73); LCMS:purity: 99.34%; MS (m/e): 418.20 (MH+).

I-436:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediaminesodium salt

¹H NMR (300 MHz, DMSO) δ 8.44 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.24(s, 2H), 6.76 (s, 1H), 6.74 (d, J=7.5, 1H), 6.66 (d, J=7.5, 1H), 2.02(s, 3H), 2.00 (s, 6H), 1.96 (s, 3H); LCMS: purity: 98.47%; MS (m/e):376.27 (MH+).

I-437:N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminesodium salt

¹H NMR (300 MHz, DMSO) δ 8.63 (s, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.28(d, J=6.6, 2H), 6.74 (s, 1H), 6.66 (s, 2H), 2.02 (s, 3H), 1.96 (s, 6H);¹⁹F NMR (282 MHz, DMSO) δ −148.58; LCMS: purity: 100%; MS (m/e): 380.11(MH+).

I-438:5-(2-(3-(difluoromethyl)-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₇F₂N₅O₂. MS (ESI) m/z 398.13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.61(s, 1H, NH), 9.43 (s, 1H, NH), 8.76 (s, 1H, NH), 7.87 (s, 1H, ArH),7.73-7.53 (m, 3H, ArH), 7.08-7.05 (m, 2H, ArH, CH), 6.88 (s, 1H, ArH),2.26 (s, 3H, CH₃), 2.09 (s, 3H, CH₃).

I-439:5-(2-(3-(fluoromethyl)-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₈FN₅O₂. MS (ESI) m/z 380.15 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.58(s, 1H, NH), 9.01 (s, 1H, NH), 8.37 (s, 1H, NH), 8.11 (s, 1H, ArH), 7.85(s, 1H, ArH), 7.63 (s, 1H, ArH), 7.48 (m, 1H, ArH), 7.29-7.20 (m, 2H,ArH), 6.98 (d, J=8.2, 1H, ArH), 5.19 (d, J=53.3, 2H, CH₂), 2.25 (s, 3H,CH₃), 2.07 (s, 3H, CH₃).

I-440:5-(2-(3-(difluoromethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 11.55 (br s, 1H), 9.19 (s, 1H), 8.38 (s, 1H),7.89 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H), 7.27 (dd, J=6.8, 2.0, 2H),7.19 (dd, J=9.1, 1.8, 1H), 6.93-6.50 (m, 2H), 3.61 (s, 3H), 2.08 (s,3H); LCMS (m/z): 414 (MH⁺).

I-441:5-(2-(4-d₃-methoxy-3-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₃D₃F₃N₅O₃. MS (ESI) m/z 435.13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ11.61 (s, 1H, NH), 9.59 (s, 1H, NH), 9.00 (s, 1H, NH), 7.85 (s, 1H,ArH), 7.75-7.68 (m, 2H, ArH), 7.23-7.21 (m, 3H, ArH), 7.10 (d, J=9.0,1H, ArH), 2.10 (s, 3H, CH₃).

I-442:5-(2-(4-(difluoromethoxy)-3-(difluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 9.26 (s, 1H), 8.38 (s, 1H),7.92-7.84 (m, 3H), 7.34-7.18 (m, 4H), 7.10 (d, J=9.2, 1H), 6.93 (t,J=26.9, 1H), 2.09 (s, 3H); LCMS (m/z): 450 (MH⁺).

I-443:5-(5-methyl-2-(4-methyl-3-(pyridin-4-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 9.99 (s, 1H), 9.41 (s, 1H), 8.58(s, 2H), 7.86 (s, 1H), 7.43-7.36 (m, 2H), 7.30 (d, J=4.9, 2H), 7.21-7.13(m, 3H), 7.02 (d, J=9.1, 1H), 2.16 (s, 3H), 2.11 (s, 3H); LCMS (m/z):425 (MH⁺).

I-444:5-(5-methyl-2-(4-methyl-3-(pyridin-3-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 9.45 (br s, 1H), 8.51 (d, J=4.8,1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.65 (d, J=8.0, 1H), 7.50-7.45 (m, 2H),7.40-7.35 (m, 1H), 7.22 (d, J=8.7, 2H), 7.21 (s, 1H), 7.12 (d, J=8.1,1H), 6.99 (d, J=8.0, 1H), 6.52 (br s, 1H), 2.12 (s, 3H), 2.09 (s, 3H);LCMS (m/z): 425 (MH⁺).

I-445:5-(2-(3-acetyl-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₁H₁₆F₃N₅O₃. MS (ESI) m/z 444.11 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.48(s, 1H, NH), 9.57 (s, 1H, NH), 8.46 (s, 1H, NH), 8.37 (d, J=5.9, 2H,ArH), 7.95 (s, 1H, ArH), 7.60 (s, H, ArH), 7.28-7.16 (m, 3H, ArH), 2.45(s, 3H, CH₃), 2.10 (s, 3H, CH₃).

I-446:5-(2-(3-(1-hydroxyethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₁H₁₈F₃N₅O₃. MS (ESI) m/z 446.10 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.31(s, 1H, NH), 8.39 (s, 1H, NH), 8.14 (s, 1H, NH), 7.97 (s, 1H, ArH), 7.91(s, 1H, ArH), 7.75 (s, 1H, ArH), 7.30-7.27 (m, 2H, ArH), 7.20-7.17 (m,1H, ArH), 7.09 (s, 1H, ArH), 4.54 (q, J=6.4, 1H, CH), 2.01 (s, 3H, CH₃),1.19 (d, J=6.4, 3H, CH₃).

I-447:5-[2-(4-d₃-Methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.66 (s, 1H), 8.88 (s, 1H), 8.40 (s, 1H),8.12 (s, 1H), 7.81 (s, 1H), 7.48 (d, J=12.2, 1H), 7.33 (s, 2H), 7.23 (s,2H), 6.72 (d, J=9.1, 1H), 2.06 (s, 3H) ppm; MS (ES) 367 (M+H);

I-448:5-[2-(3-Chloro-4-d₃-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.76-11.48 (m, 1H), 9.11 (s, 1H), 8.46 (s,1H), 8.15 (s, 1H), 7.84 (s, 2H), 7.39 (d, J=11.3, 1H), 7.25 (m, 3H),6.91 (d, J=9.0, 1H), 2.07 (s, 3H) ppm; MS (ES) 401 (M+H);

I-449:5-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.99 (s, 1H), 10.76 (s, 1H), 9.87 (s, 1H),9.84-9.67 (m, 1H), 7.91 (s, 1H), 7.42-7.24 (m, 4H), 7.18 (d, J=8.6, 1H),6.87 (d, J=8.9, 2H), 4.25 (m, 2H), 3.50 (m, 2H), 3.20 (m, 4H), 2.13 (s,3H), 1.22 (t, J=7.2, 6H) ppm; MS (ES) 449 (M+H);

I-450:N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.92 (s, 1H), 8.38 (s, 2H), 7.89 (s, 1H), 7.40(d, J=6.6, 2H), 7.34 (s, 2H), 5.64 (d, J=11.1, 2H), 2.09 (s, 3H), 2.08(s, 6H), 1.32 (s, 18H); ¹⁹F NMR (282 MHz, DMSO) δ −147.62; ³¹P NMR (121MHz, DMSO) δ −10.18; LCMS: purity: 100%; MS (m/e): 602.26 (MH+).

I-451:N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-N-4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediaminebis-sodium salt

¹H NMR (300 MHz, DMSO) δ 7.85 (br, 1H), 7.73 (br, 2H), 7.20 (br, 4H),5.42 (d, 2H), 2.13 (s, 6H), 2.09 (s, 3H); LCMS: purity: 89.35%; MS(m/e): 490.03 (MH+).

I-452:5-(2-(3,4-dimethoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 9.97 (s, 1H), 9.66 (s, 1H), 7.86(s, 1H), 7.34-7.27 (m, 3H), 6.88 (br s, 2H), 3.67 (s, 3H), 3.62 (s, 3H),2.19 (s, 3H), 2.03 (s, 3H); LRMS (M+) m/z 408.01.

I-453:5-(2-(3,4-dimethoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.97 (s, 1H), 9.60 (s, 1H), 7.85(s, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 6.89 (s, 1H), 6.86 (s, 1H), 3.67(s, 3H), 3.60 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H); LRMS(M+) m/z 422.11.

I-454:5-(2-(3,4-dimethoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-fluorobenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.12 (s, 1H), 9.97 (s, 1H), 9.50 (s, 1H), 7.89(s, 1H), 7.54 (d, J=13.0, 1H), 7.18 (s, 1H), 6.93 (br s, 2H), 3.69 (s,3H), 3.68 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H); LRMS (M+) m/z 426.08.

I-455:5-{2-[3-Chloro-4-(2-diethylamino-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.59 (s, 1H), 9.51 (s, 1H), 8.93 (s, 1H),8.44 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.19 (m, 2H), 6.73 (d, J=8.8,1H), 4.18 (m, 2H), 3.50 (m, 2H), 3.01 (m, 4H), 2.11 (s, 3H), 1.22 (t,J=7.0, 6H) ppm; MS (ES) 484 (M+H);

I-456:5-[2-(2,4-Difluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.56 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H),7.80 (s, 1H), 7.65 (dd, J=9.1, 15.4, 1H), 7.40-7.20 (m, 3H), 7.13 (d,J=8.6, 1H), 6.93 (t, J=8.7, 1H), 2.06 (s, 3H) ppm; MS (ES) 370 (M+H);

I-457:5-(5-methyl-2-(3-(1-(methylamino)ethyl)-5-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₂H₂₁F₃N₆O₂. MS (ESI) m/z 459.14 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.33(s, 1H, NH), 8.39 (s, 1H, NH), 8.21 (s, 1H, NH), 7.95-7.91 (m, 2H, ArH),7.75 (s, 1H, ArH), 7.32-7.11 (m, 4H, ArH), 3.57-3.44 (m, 4H, CH, CH₃),2.10 (s, 3H, CH₃), 1.15 (d, J=6.5, 3H, CH₃).

I-458:5-(2-(3-chloro-4,5-dimethoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 9.94 (s, 1H), 9.54 (s, 1H), 7.92(s, 1H), 7.34 (d, J=8.4, 1H), 7.29 (s, 1H), 7.25-7.22 (m, 2H), 7.00 (s,1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.19 (s, 3H); LRMS (M+) m/z 428.19.

I-459:5-(2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.85 (s, 1H), 10.22 (s, 1H), 9.79 (s, 1H),7.95 (s, 1H), 7.38 (d, J=9.1, 1H), 7.27-7.23 (m, 2H), 7.11 (s, 2H),4.07-4.03 (m, 4H), 3.84-3.79 (m, 2H), 3.63-3.60 (m, 4H), 3.32-3.21 (m,2H), 2.19 (s, 3H), 2.09 (br s, 6H); LRMS (M+) m/z 491.14.

I-460:5-(5-methyl-2-(3-(1-(methylamino)butyl)-5-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₅F₃N₆O₂. MS (ESI) m/z 487.15 (M+1)⁺.

I-461:5-(2-(3-(1-(cyclopropylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₃F₃N₆O₂. MS (ESI) m/z 485.14 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.28(s, 1H, NH), 8.40 (s, 1H, NH), 7.91 (s, 1H, ArH), 7.77 (s, 1H, ArH),7.26-7.13 (m, 5H, ArH), 4.07 (m, 1H, CH), 2.08 (s, 3H, CH₃), 1.77 (m,1H, CH), 1.13 (d, J=6.5, 3H, CH₃), 0.22-016 (m, 4H, 2CH₂).

I-462:5-(2-(3-(1-(ethylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₃F₃N₆O₂. MS (ESI) m/z 473.16 (M+1)⁺.

I-463:5-(5-methyl-2-(3-(1-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₂₅F₃N₆O₂. MS (ESI) m/z 499.16 (M+1)⁺.

I-464:5-(2-(3-(1-(azetidin-1-yl)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₃F₃N₆O₂. MS (ESI) m/z 485.14 (M+1)⁺.

I-465:5-(2-(3-(1-(cyclobutylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₂₅F₃N₆O₂. MS (ESI) m/z 499.18 (M+1)⁺.

I-466:5-[2-(2,5-Difluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.47 (s, 1H), 8.37 (s, 1H), 7.96-7.81 (m, 2H),7.27 (d, J=5.6, 2H), 7.18 (d, J=9.2, 2H), 6.77-6.62 (m, 1H), 2.09 (s,3H) ppm; MS (ES) 370 (M+H);

I-467:5-[2-(2,3-Difluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.60 (s, 1H), 8.34 (s, 1H), 7.85 (s, 1H), 7.60(s, 1H), 7.35 (d, J=10.7, 1H), 7.29 (s, 1H), 7.12 (d, J=8.6, 1H), 6.99(t, J=6.5, 2H), 2.08 (s, 3H) ppm; MS (ES) 370 (M+H);

I-468:5-[2-(2-Fluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.31 (s br, 2H), 8.16 (s, 1H), 7.90-7.76 (m,J=8.8, 2H), 7.44-7.28 (m, J=9.8, 2H), 7.24-7.08 (m, 2H), 7.07-6.92 (m,2H), 2.07 (s, 5H) ppm; MS (ES) 352 (M+H);

I-469:N-Cyclobutyl-3-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-5-trifluoromethyl-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.64 (s, 1H), 10.89 (s, 1H), 9.73 (s, 1H),8.81 (d, J=7.5, 1H), 8.10-7.90 (m, 3H), 7.82 (s, 1H), 7.15 (s, 3H), 4.38(dd, J=8.1, 16.1, 1H), 2.12 (s, 3H), 2.10-1.92 (m, 4H), 1.76-1.57 (m,2H) ppm; MS (ES) 499 (M+H);

I-470:5-[2-(4-Fluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.62 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H),8.11 (s, 1H), 7.85 (s, 1H), 7.71-7.53 (m, 2H), 7.31 (d, J=5.3, 1H), 7.23(d, J=9.1, 1H), 6.96 (t, J=8.9, 2H), 6.54 (s, 1H), 2.07 (s, 3H) ppm; MS(ES) 352 (M+H);

I-471:5-(2-(4-fluoro-3-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 9.90 (br s, 1H), 9.29 (br s,1H), 8.58 (d, J=6.1, 2H), 7.88 (s, 1H), 7.80 (d, J=5.9, 1H), 7.55-7.46(m, 1H), 7.38 (d, J=4.7, 2H), 7.31-7.22 (m, 1H), 7.18 (s, 1H), 7.17 (d,J=9.7, 1H), 7.02 (d, J=8.4, 1H), 2.12 (s, 3H); LCMS (m/z): 429 (MH⁺).

I-472:5-(2-(4-fluoro-3-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.97 (br s, 1H), 9.35 (br s,1H), 8.55 (d, J=4.8, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.75 (t, J=7.8,2H), 7.43 (dd, J=14.9, 9.8, 2H), 7.25 (t, J=9.8, 1H), 7.17 (s, 1H), 7.16(d, J=7.5, 2H), 6.98 (d, J=8.9, 1H), 2.12 (s, 3H); LCMS (m/z): 429(MH⁺).

I-473:5-(2-(3-(1-(isopropylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₅F₃N₆O₂. MS (ESI) m/z 486.49 (M+1)⁺.

I-474:5-(2-(3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.89 (s, 1H), 9.65 (s, 1H), 7.89(s, 1H), 7.10 (s, 2H), 7.04 (s, 2H), 6.72 (s, 1H), 2.32 (s, 3H), 2.18(s, 3H), 2.08 (s, 6H); LRMS (M+) m/z 376.24.

I-475:7-methyl-5-(5-methyl-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 9.98 (s, 1H), 9.67 (s, 1H), 7.87(s, 1H), 7.11 (s, 2H), 7.05 (s, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 2.07(s, 3H), 2.06 (s, 6H); LRMS (M+) m/z 390.28.

I-476:5-(2-(4-fluoro-3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.94 (s, 1H), 9.59 (s, 1H), 7.88(s, 1H), 7.14 (d, J=6.4, 2H), 7.10 (br s, 2H), 2.31 (s, 3H), 2.17 (s,3H), 2.05 (br s, 6H); LRMS (M+) m/z 394.25.

I-477:5-[5-Methyl-2-(2,3,4,5-tetrafluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.02-8.81 (m, 1H), 8.49 (s, 1H), 8.27 (s, 1H),7.98-7.77 (m, 2H), 7.31 (s, 1H), 7.28-7.13 (m, J=9.6, 2H), 2.09 (s, 3H)ppm; MS (ES) 406 (M+H);

I-478:N2-(3-cyano-5-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.50 (s, 1H), 9.60 (s, 1H), 8.52 (s, 1H), 8.03(s, 1H), 7.94 (s, 1H), 7.68 (s, 1H), 7.22 (m, 3H), 7.15 (t, J=73, 1H),7.08 (s, 1H), 2.10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −98.22 (d, J=73);LCMS: purity: 98.34%; MS (m/e): 425.09 (MH+).

I-479:5-methyl-N2-(3-methyl-5-trifluoromethyl)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 9.30 (s, 1H), 8.45 (s, 1H), 7.91(s, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.24 (m, 3H), 6.92 (s, 1H), 2.14(s, 3H), 2.09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −76.92; LCMS: purity:100%; MS (m/e): 416.02 (MH+).

I-480:5-[5-Methyl-2-(2,3,5-trifluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.87-8.65 (m, 1H), 8.48 (s, 1H), 7.88 (s, 1H),7.82-7.67 (m, 1H), 7.25 (s, 1H), 7.20 (d, J=8.5, 1H), 7.12 (d, J=7.5,1H), 7.01-6.84 (m, 1H), 2.09 (s, 3H) ppm; MS (ES) 388 (M+H);

I-481:5-[5-Methyl-2-(2,4,5-trifluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.45 (s, 1H), 8.37 (s, 1H), 8.09-7.91 (m, 1H),7.84 (s, 1H), 7.48 (dd, J=10.8, 18.5, 1H), 7.17 (m, 2H), 7.07 (d, J=8.5,1H), 2.07 (s, 3H) ppm; MS (ES) 388 (M+H);

I-482:5-(5-methyl-2-(3-methyl-4-(pyridin-4-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 9.45 (d, J=7.2, 2H), 8.37 (d, J=9.9, 2H), 8.12(d, J=7.2, 2H), 7.48 (s, 1H), 7.40 (d, J=8.5, 1H), 7.26 (s, 2H),6.61-6.53 (m, 2H), 6.19 (s, 2H), 2.38 (s, 3H), 2.29 (s, 3H); LCMS (m/z):425 (MH⁺).

I-483:5-(5-methyl-2-(3-methyl-4-(pyridin-3-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.83 (s, 1H), 9.14 (s, 1H),8.57-8.48 (m, 2H), 7.91 (s, 1H), 7.74 (d, J=8.4, 1H), 7.51 (s, 1H),7.48-7.37 (m, 2H), 7.31-7.24 (m, 3H), 7.07 (d, J=8.4, 1H), 2.13 (s, 3H),2.00 (s, 3H); LCMS (m/z): 424 (MH⁺).

I-484:5-(2-(3-fluoro-4-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 9.44 (s, 1H), 9.41 (s, 1H), 9.18 (s, 1H),8.29-8.25 (m, 3H), 7.81 (t, J=8.8, 1H), 7.09 (s, 1H), 6.97-6.84 (m, 4H),6.58 (d, J=8.7, 1H), 6.48 (d, J=15.7, 1H), 2.27 (s, 3H); LCMS (m/z): 429(MH⁺).

I-485:N2-(3,4-dimethoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 7.87 (s, 1H), 7.40 (br, 2H),7.20 (s, 3H), 3.72 (s, 3H), 3.61 (s, 3H), 2.12 (s, 3H); ¹⁹F NMR (282MHz, DMSO) δ −75.83; LCMS: purity: 100%; MS (m/e): 462.24 (MH+).

I-486:5-(2-(4-methoxy-3-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 11.49 (s, 1H), 9.09 (s, 1H), 8.47 (d, J=5.8,3H), 7.84 (s, 1H), 7.68 (s, 1H), 7.59 (d, J=9.0, 1H), 7.32 (s, 2H), 7.26(d, J=7.8, 2H), 7.02 (d, J=9.0, 1H), 6.98 (d, J=9.0, 1H), 3.72 (s, 3H),2.07 (s, 3H); LCMS (m/z): 441 (MH⁺).

I-487:5-(2-(4-methoxy-3-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 8.91 (s, 1H), 8.50 (s, 1H), 8.43 (d, J=4.5,1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.71 (d, J=7.9, 1H), 7.66(s, 1H), 7.61 (d, J=9.0, 1H), 7.35-7.25 (m, 3H), 6.96 (dd, J=12.8, 9.1,2H), 3.69 (s, 3H), 2.06 (s, 3H); LCMS (m/z): 441 (MH⁺).

I-488:5-(2-(3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)-7-fluorobenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 9.87 (s, 1H), 9.51 (s, 1H), 7.93(s, 1H), 7.48 (d, J=12.2, 1H), 7.17 (s, 1H), 7.10 (s, 2H), 6.75 (s, 1H),2.19 (s, 3H), 2.16 (br s, 6H); LRMS (M+) m/z 380.06.

I-489:7-fluoro-5-(5-methyl-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.12 (s, 1H), 9.85 (s, 1H), 9.52 (s, 1H), 7.90(s, 1H), 7.49 (d, J=12.4, 1H), 7.17 (s, 1H), 7.10 (s, 2H), 2.18 (s, 3H),2.14 (s, 6H), 2.11 (s, 3H); LRMS (M+) m/z 394.10.

I-490:7-fluoro-5-(2-(4-fluoro-3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 9.93 (s, 1H), 9.50 (s, 1H), 7.92(s, 1H), 7.48 (d, J=12.4, 1H), 7.20-7.17 (m, 3H), 2.18 (s, 3H), 2.13 (brs, 6H); LRMS (M+) m/z 398.06.

I-491:5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.91 (s, 1H), 9.48 (br s, 1H),7.87 (s, 1H), 7.15 (s, 1H), 7.12 (br s, 1H), 7.04 (dd, J=7.2, 1.4, 1H),6.95 (d, J=5.2, 1H), 3.63 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 2.06 (brs, 3H); LRMS (M+) m/z 410.02.

I-492:7-fluoro-5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.10 (s, 1H), 9.88 (s, 1H), 9.38 (s, 1H), 7.92(s, 1H), 7.53 (d, J=13.0, 1H), 7.19 (s, 1H), 7.07 (br d, J=6.7, 1H),7.01 (br d, J=5.1, 1H), 3.71 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H); LRMS(M+) m/z 414.05.

I-493:N2-(3,4-dimethyl-2-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.80(s, 1H), 7.49 (t, J=8.4, 1H), 7.38 (d, J=8.4, 1H), 7.29 (s, 1H), 7.09(d, J=8.7, 1H), 6.80 (d, J=8.4, 1H), 2.18 (s, 3H), 2.08 (s, 3H), 2.06(s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −145.07; LCMS: purity: 100%; MS(m/e): 380.15 (MH+).

I-494:5-(2-(3-methoxy-4-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 9.28 (d, J=7.4, 2H), 8.46 (s, 1H), 8.32 (d,J=7.4, 3H), 7.68 (d, J=8.8, 1H), 7.46 (s, 1H), 7.19 (s, 2H), 6.70 (s,2H), 6.36 (d, J=8.8, 1H), 6.33 (s, 1H), 3.86 (s, 3H), 2.27 (s, 3H); LCMS(m/z): 441 (MH⁺).

I-495:N2-(3-chloro-5-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.78 (br, 1H), 9.08 (br, 1H),7.91 (s, 1H), 7.56 (s, 1H), 7.25 (d, 2H), 7.19 (d, 2H), 7.12 (t, J=73,1H), 6.78 (s, 1H), 2.12 (s, 3H); LCMS: purity: 97.32%; MS (m/e): 434.02(MH+).

I-496:5-[2-(3-Chloro-4-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.59 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H),7.94-7.77 (m, 2H), 7.38 (d, J=9.0, 1H), 7.25 (d, J=10.5, 3H), 6.93 (d,J=9.1, 1H), 3.74 (s, 3H), 2.07 (s, 3H) ppm; MS (ES) 398 (M+H);

I-497:5-[2-(3-Chloro-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.55 (s br, 1H), 9.59 (s, 1H), 8.53 (s, 1H),8.10 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.31-7.07 (m, 3H), 2.09 (s,3H) ppm; MS (ES) 436/438 (M+H);

I-498:5-[2-(2-Methoxy-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.52 (s, 1H), 8.50 (d, J=10.0, 2H), 7.92 (s,1H), 7.59 (s, 1H), 7.29 (s, 1H), 7.26-7.04 (m, 3H), 3.91 (s, 3H), 2.09(s, 3H) ppm; MS (ES) 432 (M+H);

I-499:5-(2-(o-toluidino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₁₉H₁₇N₅O₂. MS (ESI) m/z 348.23 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.20(s, 1H, NH), 8.11 (s, 1H, NH), 7.98 (s, 1H, ArH), 7.78 (s, 1H, ArH),7.53 (d, J=7.9, 1H, ArH), 7.36-7.28 (m, 1H, ArH), 7.14 (s, 1H, ArH),7.11-7.04 (m, 3H, ArH), 6.96-6.91 (m, 1H, ArH), 2.16 (s, 3H, CH₃), 2.05(s, 3H, CH₃).

I-500:5-(2-(2,3-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₉N₅O₂. MS (ESI) m/z 362.21 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.14(s, 1H, NH), 8.12 (s, 1H, NH), 8.11 (s, 1H, NH, ArH), 7.74 (s, 1H, ArH),7.39 (d, J=8.8, 1H, ArH), 7.26-7.21 (m, 2H, ArH), 7.02-6.97 (m, 2H,ArH), 6.90-6.88 (m, 1H, ArH), 2.18 (s, 3H, CH₃), 2.03 (s, 3H, CH₃), 2.00(s, 3H, CH₃).

I-501:5-(2-(2,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₉N₅O₂. MS (ESI) m/z 362.21 (M+1)⁺.

I-502:5-(2-(2-ethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₉N₅O₂. MS (ESI) m/z 362.21 (M+1)⁺.

I-503:5-(2-(3-ethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₉N₅O₂. MS (ESI) m/z 362.21 (M+1)⁺.

I-504:5-(2-(4-ethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₉N₅O₂. MS (ESI) m/z 362.21 (M+1)⁺.

I-505:5-(2-(3-fluoro-4-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-onetrifluoroacetic acid salt

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.78 (s, 1H), 9.63 (d, J=6.4,1H), 9.49 (s, 1H), 8.89 (d, J=8.4, 1H), 8.43 (s, 1H), 8.27-8.17 (m, 1H),7.50-7.25 (m, 5H), 6.57 (dd, J=8.5, 1.9, 1H), 6.48 (d, J=14.6, 1H), 2.32(s, 3H); LCMS (m/z): 429 (MH⁺).

I-506:5-(2-(3-methoxy-4-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneformate salt

¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.41 (s, 1H), 9.64 (s, 1H),8.77 (s, 1H), 8.61 (d, J=5.1, 1H), 8.14 (d, J=7.3, 1H), 7.93 (s, 1H),7.67 (dd, J=7.6, 5.4, 1H), 7.28 (d, J=4.2, 2H), 7.26 (s, 2H), 7.22 (d,J=5.7, 2H), 3.49 (s, 3H), 2.15 (s, 3H); LCMS (m/z): 441 (MH⁺).

I-507:5-(2-(2,4-difluoro-3-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.91 (s, 1H), 9.62 (s, 1H), 7.90(s, 1H), 7.32 (td, J=8.8, 5.6, 1H), 7.19-7.12 (m, 1H), 7.09 (br s, 1H),7.06 (d, J=1.7, 1H), 3.88 (s, 3H), 2.25 (s, 3H), 2.18 (br s, 3H); LRMS(M+) m/z 414.05.

I-508:5-(2-(2,4-difluoro-3-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)-7-fluorobenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.06 (s, 1H), 9.72 (s, 1H), 9.40 (s, 1H), 7.93(s, 1H), 7.42 (d, J=12.6, 1H), 7.36-7.28 (m, 1H), 7.19 (dd, J=10.9, 1.7,1H), 7.14 (d, J=1.7, 1H), 3.91 (s, 3H), 2.18 (s, 3H); LRMS (M+) m/z418.06.

I-509:5-(2-(4-(6-chloropyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-onetrifluoroacetate salt

¹H NMR (300 MHz, DMSO) δ 11.80 (s, 1H), 10.53 (s, 1H), 9.67 (s, 1H),8.66 (s, 1H), 8.06 (d, J=8.5, 1H), 7.94 (s, 1H), 7.57-7.55 (m, 5H), 7.36(d, J=8.5, 1H), 7.29-7.21 (m, 2H), 2.15 (s, 3H); LCMS (m/z): 445 (MH⁺).

I-510:5-(2-(4-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-onetrifluoroacetate salt

¹H NMR (300 MHz, DMSO) δ 11.85 (s, 1H), 10.64 (s, 1H), 9.87 (s, 1H),8.43 (s, 1H), 7.93 (s, 1H), 7.88-7.79 (m, 1H), 7.51-7.43 (m, 4H), 7.36(d, J=8.5, 1H), 7.27 (d, J=1.6, 1H), 7.21 (d, J=8.6, 1H), 7.04 (d,J=8.7, 1H), 4.45 (d, J=12.6, 2H), 3.51 (d, J=9.2, 2H), 3.14 (dd, J=24.6,12.0, 4H), 2.84 (s, 3H), 2.15 (s, 3H); LCMS (m/z): 509 (MH⁺).

I-511:5-(2-(4-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-onetrifluoroacetate salt

¹H NMR (300 MHz, DMSO) δ 11.85 (s, 1H), 10.67 (s, 1H), 9.84 (s, 1H),8.40 (s, 1H), 7.97-7.92 (m, 2H), 7.50 (s, 4H), 7.36 (d, J=8.5, 1H), 7.27(s, 1H), 7.22 (d, J=8.6, 1H), 6.88 (d, J=8.6, 1H), 4.36 (t, J=6.1, 2H),3.27-3.17 (m, 2H), 2.81 (d, J=4.1, 6H), 2.16-2.07 (m, 5H); LCMS (m/z):512 (MH⁺).

I-512:5-(5-methyl-2-(4-(6-morpholinopyridin-3-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-onetrifluoroacetate salt

¹H NMR (300 MHz, DMSO) δ 11.81 (s, 1H), 10.40 (s, 1H), 9.79 (s, 1H),8.39 (s, 1H), 7.89 (s, 1H), 7.87 (d, J=9.0, 2H), 7.47 (q, J=8.6, 4H),7.35 (d, J=8.4, 1H), 7.28-7.16 (m, 2H), 6.96 (d, J=9.0, 1H), 3.73-3.68(m, 4H), 3.52-3.47 (m, 4H), 2.15 (s, 3H), LCMS (m/z): 496 (MH⁺).

I-513:5-(2-(2-fluoro-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₁₉H₁₆FN₅O₂. MS (ESI) m/z 366.19 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.37(s, 1H, NH), 8.23 (s, 1H, NH), 8.11 (s, 1H, NH), 7.83 (s, 1H, ArH),7.68-7.64 (m, 1H, ArH), 7.37-7.29 (m, 2H, ArH), 7.12 (d, J=8.6, 1H,ArH), 6.92-6.84 (m, 2H, ArH), 2.19 (s, 3H, CH₃), 2.07 (s, 3H, CH₃).

I-514:5-(2-(2-fluoro-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₁₉H₁₆FN₅O₂. MS (ESI) m/z 366.20 (M+1)⁺.

I-515:5-(2-(2-fluoro-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₁₉H₁₆FN₅O₂. MS (ESI) m/z 366.16 (M+1)⁺.

I-516:N2-(3-difluoromethoxy-5-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 7.88 (s, 1H), 7.26-7.11 (m, 5H),7.00 (t, J=74, 1H), 6.59 (s, 1H), 2.12 (s, 3H), 2.08 (s, 3H); LCMS:purity: 94.88%; MS (m/e): 414.31 (MH+).

I-517:5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N-2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediaminecalcium salt

¹H NMR (300 MHz, DMSO) δ 8.08 (br, 1H), 7.84 (br, 1H), 7.60 (br, 2H),7.21 (br, 2H), 5.44 (d, 2H), 2.14 (s, 6H), 2.09 (s, 3H), 2.02 (s, 3H);LCMS: purity: 100%; MS (m/e): 486.39 (MH+).

I-518:5-[5-Methyl-2-(2-methyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.40 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.79(s, 1H), 7.73 (d, J=7.8, 1H), 7.39 (d, J=7.6, 1H), 7.37-7.20 (m, 3H),7.02 (d, J=8.7, 1H), 2.23 (s, 3H), 2.05 (s, 3H) ppm; MS (ES) 416 (M+H);

I-519:5-(2-(5-acetyl-2-fluorophenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₆FN₅O₃. MS (ESI) m/z 394.33 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.46(s, 1H, NH), 8.58 (s, 1H, NH), 8.32-8.28 (m, 2H, NH, ArH), 7.86 (s, 1H,ArH), 7.64-7.60 (m, 1H, ArH), 7.37-7.29 (m, 3H, ArH), 7.06 (d, J=8.6,7H, ArH), 2.35 (s, 3H, CH₃), 2.08 (s, 3H, CH₃).

I-520:5-(2-(2-chlorophenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.62 (s, 2H), 7.93 (s, 1H), 7.72(d, J=7.7, 1H), 7.60 (d, J=7.7, 1H), 7.37-7.24 (m, 6H), 2.19 (s, 3H);LRMS (M+) m/z 367.98.

I-521:5-(2-(2-chloro-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.63 (s, 1H), 9.44 (s, 1H), 7.94(s, 1H), 7.54 (s, 1H), 7.47 (d, J=8.2, 1H), 7.26-7.25 (m, 3H), 7.07 (d,J=8.0, 1H), 2.19 (s, 3H), 2.13 (s, 3H); LRMS (M+) m/z 382.01.

I-522:N4-(7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-5-methyl-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.92 (br, 1H), 8.79 (s, 1H), 8.36 (s, 1H),7.87 (s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 7.24 (s, 2H), 2.06 (s, 3H),2.01 (s, 6H), 1.98 (s, 3H); LCMS: purity: 93.26%; MS (m/e): 410.39(MH+).

I-523:5-(2-(2-fluoro-5-(1-hydroxyethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₈FN₅O₃. MS (ESI) m/z 396.36 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ8.25-8.21 (m, 3H, 3NH), 7.82 (s, 1H, ArH), 7.63 (d, J=8.0, 1H, ArH),7.37-7.30 (m, 2H, ArH), 7.16-7.09 (m, 2H, ArH), 7.00-6.95 (m, 1H, ArH),2.06 (s, 3H, CH₃), 1.17 (d, J=5.3, 3H, CH₃).

I-524:N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3,4,5-trimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

1H NMR (300 MHz, DMSO) δ 8.88 (s, 1H), 8.45 (br, 1H), 8.42 (s, 1H), 7.92(s, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 5.64 (d, J=10.8, 2H), 2.12 (s, 6H),2.09 (s, 3H), 2.02 (s, 3H), 1.33 (s, 18H); ³¹P NMR (121 MHz, DMSO) δ−10.08; LCMS: purity: 94.23%; MS (m/e): 632.57 (MH+).

I-525:N4-[7-chloro-3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-5-methyl-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine

1H NMR (300 MHz, DMSO) δ 5.50 (d, 2H), 2.12 (s, 6H), 2.07 (s, 3H), 2.03(s, 3H); LCMS: purity: 100%; MS (m/e): 520.41 (MH+).

I-526:5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N-2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediaminemagnesium salt

¹H NMR (300 MHz, DMSO) δ 7.60 (br, 2H), 7.20 (br, 4H), 5.42 (d, 2H),2.06 (s, 6H), 2.02 (s, 6H); LCMS: purity: 94.72%; MS (m/e): 486.41(MH+).

I-527:5-[2-(4-Iodo-3,5-dimethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.77 (s, 1H), 10.27-10.04 (m, 1H), 9.74-9.54(m, 1H), 7.89 (s, 1H), 7.31 (s, 1H), 7.20 (s, 3H), 2.14 (s, 6H), 2.12(s, 3H) ppm; MS (ES) 488 (M+H);

I-528:N4-[7-chloro-3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-5-methyl-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediaminebis-sodium salt

LCMS: purity: 91.57%; MS (m/e): 520.38 (MH+).

I-529:5-(2-(3,5-dimethoxy-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 10.04 (s, 1H), 9.54 (s, 1H),7.86 (s, 1H), 7.35-7.27 (m, 3H), 6.74 (s, 2H), 3.57 (s, 6H), 2.19 (s,3H), 1.97 (s, 3H); LRMS (M+) m/z 408.40.

I-530:5-(2-(2-fluoro-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₈FN₅O₂. MS (ESI) m/z 380.21 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.27(s, 1H, NH), 8.14 (s, 1H, NH), 8.06 (s, 1H, NH), 7.80 (s, 1H, ArH), 7.47(d, J=8.4, 1H, ArH), 7.36-7.28 (m, 2H, ArH), 7.11 (d, J=8.6, 1H, ArH),6.97 (d, J=12.2, 1H, ArH), 2.12 (s, 3H, CH₃), 2.05 (s, 3H, CH₃), 1.96(s, 3H, CH₃).

I-531:5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N-2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediaminebis-choline salt

¹H NMR (300 MHz, DMSO) δ 9.28 (br, 1H), 7.82 (s, 1H), 7.66 (s, 2H), 7.18(s, 2H), 5.39 (d, J=7.2, 2H), 3.77 (s, 4H), 3.41 (t, J=4.8, 4H), 3.04(s, 18H), 2.14 (s, 6H), 2.08 (s, 3H), 2.01 (s, 3H); LCMS: purity:95.26%; MS (m/e): 486.39 (MH+).

I-532:5-(2-(2-fluoro-4-methyl-3-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₅F₄N₅O₂. MS (ESI) m/z 434.16 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.52(s, 1H, NH), 8.53 (s, 1H, NH), 8.33 (s, 1H, NH), 7.99-7.92 (m, 1H, ArH),7.84 (s, 1H, ArH), 7.34-7.31 (m, 1H, ArH), 7.26 (s, 1H, ArH), 7.13-7.10(m, 1H, ArH), 7.05 (d, J=8.6, 1H, ArH), 2.38 (s, 3H, CH₃), 2.07 (s, 3H,CH₃).

I-533:5-(2-(2-fluoro-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 8.45 (br s, 1H), 8.24 (br s,1H), 7.85 (s, 1H), 7.45 (dd, J=6.7, 3.2, 1H), 7.29 (d, J=5.9, 1H), 7.28(s, 1H), 7.10 (dd, J=20.6, 9.3, 2H), 6.51-6.45 (m, 1H), 3.54 (s, 3H),2.08 (s, 3H); LCMS (m/z): 382 (MH⁺).

I-534:5-(2-(2-fluoro-3,4,5-trimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₁H₁₈FN₅O₂. MS (ESI) m/z 394.38 (M+1)⁺.

I-535:5-(2-(3-methoxy-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.83 (s, 1H), 10.22 (s, 1H), 9.74 (s, 1H),7.89 (s, 1H), 7.35-7.26 (m, 3H), 6.91 (s, 1H), 6.80 (s, 1H), 3.57 (s,3H), 2.18 (s, 3H), 2.02 (s, 6H); LRMS (M+) m/z 392.26.

I-536: Sodium(5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)methylphosphate

¹H NMR (300 MHz, D₂O) δ 7.72 (s, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 6.83(s, 1H), 6.67 (s, 1H), 6.40 (s, 1H), 5.41 (d, J=5.9, 2H), 3.60 (s, 3H),2.19 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H); LRMS (M−) m/z 500.17.

I-537:N2-(3,4-dimethyl-5-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.02 (s, 1H), 8.38 (s, 1H), 7.86(s, 1H), 7.39 (d, J=12.6, 1H), 7.26-7.20 (m, 3H), 7.14 (s, 1H), 2.07 (s,3H), 2.04 (s, 3H), 1.98 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −133.44;LCMS: purity: 99.82%; MS (m/e): 380.40 (MH+).

I-538: Sodium(5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methylphosphate

¹H NMR (300 MHz, D₂O) δ 7.67 (s, 1H), 7.40 (dd, J=8.7, 2.1, 1H), 7.32(d, J=1.4, 1H), 7.14 (d, J=8.7, 1H), 6.80-6.74 (m, 2H), 5.41 (d, J=6.1,2H), 3.64 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H); LRMS (M−) m/z 504.10.

II-1:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-dimethylaminopyridin-3-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 378.06 (M+H), 376.10 (M−H); ¹H NMR (300 MHz, DMSO) δ 11.62 (s,1H), 9.88 (s, 1H), 9.59 (s, 1H), 8.20-8.06 (m, 1H), 8.08-7.93 (m, 1H),7.92-7.77 (m, 2H), 7.24 (m, 2H), 6.98-6.83 (m, 1H), 3.06 (d, J=4.2, 6H),2.12 (s, 3H) ppm.

II-2:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (DMSO d₆, 300 MHz): δ 8.54 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H,J=1.8 Hz), 7.77 (s, 1H), 7.72 (dd, 1H, J=2.2 and 8.8 Hz), 7.33 (d, 1H,J=8.4 Hz), 7.29 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 6.36 (d, 1H, J=9.0 Hz),4.48 (s, 1H), 3.52 (s, 1H), 3.38 (d, 1H, J=9.9 Hz), 3.25 (d, 1H, J=9.6Hz), 2.82 (d, 1H, J=9.6 Hz), 2.54 (s, 1H), 2.32 (s, 3H), 2.06 (s, 3H),1.89 (d, 1H, J=9.6 Hz), 1.76 (d, 1H, J=9.3 Hz).

II-3:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 447.11 (M+H), 445.23 (M−H); ¹H NMR (300 MHz, DMSO) δ 8.61 (s,1H), 8.25 (s, 1H), 8.16 (m, 2H), 7.78 (m, 3H), 7.33 (s, 3H), 7.24-7.10(m, 1H), 6.58-6.43 (m, 1H), 3.75 (m, 2H), 3.50 (m, 2H), 2.86 (m, 4H),2.48 (m, 6H), 2.01 (m, 2H) ppm.

II-4:N4-(3-n-propylbenzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.82 (s, NH), 9.43 (s, NH), 8.24 (s, 1H), 7.88(s, 1H), 7.61 (d, J=8.0, 1H), 7.46 (s, 1H), 7.29 (t, J=11.1, 1H), 6.81(d, J=9.3, 1H), 3.39-3.70 (m, 10H), 2.83 (s, 3H), 2.12 (s, 3H), 1.61(tq, J=12.9, 17.3, 2H), 0.81 (t, J=7.4, 3H).

II-5:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-tert-butyloxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, NH), 8.84 (s, NH), 8.39 (s, NH), 8.26(s, H), 8.10 (s, H), 7.80 (s, 1H), 7.18 (d, J=12.4, H), 7.02 (d, J=9.0,H), 6.86 (d, J=5.5, H), 6.70 (d, J=12.8, H), 3.28-3.44 (m, 8H), 2.06 (s,3H), 1.40 (s, 9H).

II-6:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-methylpiperidin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, NH), 9.50 (s, NH), 9.21 (s, NH), 8.07(s, 1H), 7.81 (d, J=23.2, 1H), 7.61 (d, J=9.0, 1H), 7.28 (d, J=38.7,3H), 6.81 (d, J=8.9, 1H), 3.65-3.17 (m, 2H), 2.75 (t, J=12.7, 2H), 2.09(s, 3H), 1.73-1.45 (m, 3H), 1.06 (t, J=14.0, 2H), 0.89 (d, J=6.2, 3H).

II-7:N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-isopropylbenzo[d]oxazol-2(3H)-on-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 12.01 (s, NH), 9.73 (s, NH), 8.12 (s, 1H), 7.85(s, 1H), 7.64 (d, J=11.0, 1H), 7.45 (s, 1H), 7.31 (s, 2H), 6.84 (d,J=6.1, 1H), 4.82 (s, 1H), 4.41 (s, 1H), 4.25 (d, J=9.3, 2H), 3.96 (m,1H), 3.02 (d, J=15.6, 4H), 2.83 (s, 2H), 2.13 (s, 3H), 1.37 (d, J=6.7,6H).

II-8:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-trifluoromethoxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 8.80 (s, NH), 8.40-8.21 (m, 2NH), 8.11 (s, 1H),7.96-7.74 (m, 2H), 7.30 (s, 2H), 7.19 (d, J=8.5, 1H), 6.73 (d, J=9.1,1H), 3.73-3.25 (m, 8H), 2.06 (s, 3H).

II-9:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-methoxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.03 (s, NH), 8.72 (s, NH), 8.29 (s, NH), 8.15(s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.44-7.09 (m, 3H), 7.02 (s, 1H),3.64-3.40 (m, 11H), 2.08 (s, 3H).

II-10:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 8.89 (s, NH), 8.79 (s, NH), 8.23 (s, NH), 8.18(s, 1H), 7.82 (d, J=15.2, 2H), 7.38 (dd, J=17.9, 48.5, 2H), 7.15 (d,J=6.1, 1H), 6.64 (d, J=9.2, 1H), 3.50-3.22 (m, 4H), 2.84-2.74 (m, 4H),2.05 (s, 3H), 1.05 (s, NH).

II-11:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(3-methyl-4-tert-butoxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 12.01 (s, NH), 11.55 (s, NH), 8.76 (s, NH),8.24 (s, 1H), 7.79 (s, 2H), 7.32 (d, J=11.4, 2H), 7.17 (d, J=8.4, 1H),6.68 (d, J=9.6, 1H), 3.95 (dd, J=11.5, 21.3, 2H), 3.76 (d, J=13.1, 1H),3.67-3.41 (m, 1H), 3.09 (t, J=12.2, 1H), 2.89 (dd, J=4.0, 13.0, 1H),2.67 (dd, J=6.8, 16.2, 1H), 2.06 (s, 3H), 1.40 (s, 9H), 1.09 (d, J=6.6,3H).

II-12:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 8.93 (s, NH), 8.79 (s, NH), 8.40 (s, NH), 8.21(s, 1H), 7.92-7.75 (m, 2H), 7.39-7.24 (m, 2H), 7.18 (d, J=8.6, 1H), 6.75(d, J=9.0, 1H), 4.25-3.94 (m, 1H), 3.21 (d, J=9.8, 1H), 3.10 (s, 1H),2.88 (dd, J=13.5, 22.1, 3H), 2.64 (dd, J=13.3, 26.8, 1H), 2.06 (s, 3H),1.19 (d, J=6.2, 3H).

II-13:N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H),7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d,J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H₂O), 2.44-2.41 (m, 4H),2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.

II-14:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 437.54; ¹H NMR (300 MHz, DMSO) δ 11.71 (br s, 1H), 9.31(s, 1H), 8.95 (s, 1H), 8.28-8.27 (m, 1H), 8.05 (d, J=3.7, 1H), 7.84 (brd, J=8.9, 1H), 7.46 (d, J=8.9, 1H), 7.36 (br s, 1H), 7.21 (d, J=8.8,1H), 6.77 (d, J=8.8, 1H), 3.40-3.36 (m, 4H, overlapped with H₂O),2.44-2.41 (m, 4H), 2.25 (s, 3H).

II-15:N4-(benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 432.55; ¹H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 10.50 (s,1H), 8.63 (s, 1H), 8.28 (d, J=2.3, 1H), 8.17 (s, 1H), 7.86 (dd, J=2.3,9.1, 1H), 7.79 (s, 1H), 7.19 (d, J=8.3, 1H), 7.12 (s, 1H), 6.87 (d,J=8.3, 1H), 6.64 (d, J=9.1, 1H), 3.37-3.34 (m, 4H, overlapped with H₂O),2.44-2.41 (m, 4H), 2.24 (s, 3H), 2.09 (s, 3H).

II-16:N4-(benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H),8.85 (s, 1H), 8.27 (br d, J=2.3, 1H), 8.00 (br d, J=3.8, 1H), 7.84 (dd,J=2.3, 9.1, 1H), 7.30 (dd, J=1.7, 8.2, 1H), 7.17 (d, J=1.7, 1H), 6.86(d, J=8.2, 1H), 6.73 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped withH₂O), 2.44-2.41 (m, 4H), 2.25 (s, 3H); LCMS (M+) m/z 436.50.

II-17:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 420.01; ¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.99 (s,1H), 9.72 (br s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.61 (d, J=8.8, 1H),7.31-7.20 (m, 3H), 6.88 (d, J=8.8, 1H), 3.74-3.71 (m, 4H), 3.46-3.43 (m,4H), 2.18 (s, 3H).

II-18:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 423.98; ¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.82 (s,1H), 9.61 (s, 1H), 8.35 (s, 1H), 8.19 (d, J=4.1, 1H), 8.02 (br d, J=9.0,1H), 7.41-7.39 (m, 3H), 7.29-7.22 (m, 3H), 3.79-3.76 (m, 4H), 3.54-3.51(m, 4H).

II-19:N4-(benzimidazolin-2-on-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.61 (s, 2H), 9.79 (br s, 1H), 9.55 (br s,1H), 8.31 (s, 1H), 8.13 (d, J=4.4, 1H), 7.92 (br d, J=8.8, 1H), 7.22 (d,J=8.1, 1H), 7.18 (s, 1H), 7.10 (br d, J=8.8, 1H), 6.89 (d, J=8.1, 1H),3.78-3.75 (m, 4H), 3.50-3.47 (m, 4H); LCMS (M+) m/z 423.00.

II-20:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazino)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (M+) m/z 460.54; ¹H NMR (300 MHz, DMSO) δ 8.68 (s, 1H), 8.39 (br s,1H), 8.27 (s, 1H), 7.82 (s, 1H), 7.71 (br d, J=8.4, 1H), 7.53 (s, 1H),7.23 (br d, J=9.0, 1H), 7.09 (d, J=8.4, 1H), 6.65 (d, J=9.0, 1H),3.37-3.34 (m, 7H, partially overlapped with H₂O), 3.27 (s, 3H),2.43-2.40 (m, 4H), 2.25 (s, 3H), 2.12 (s, 3H).

II-21:N4-(1,3-dimethylbenzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazino)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

LCMS (M+) m/z 464.49; ¹H NMR (300 MHz, DMSO) δ 9.28 (s, 1H), 8.90 (s,1H), 8.38 (d, J=2.1, 1H), 8.03 (d, J=3.8, 1H), 7.70 (d, J=8.3, 1H), 7.61(s, 1H), 7.27 (d, J=8.8, 1H), 7.09 (d, J=8.3, 1H), 6.72 (d, J=8.8, 1H),3.37 (m, 7H, overlapped with H₂O), 3.27 (s, 3H), 2.48-2.36 (m, 4H), 2.25(s, 3H).

II-22:N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 9.83 (s, 1H), 8.21 (s, 1H), 7.86(s, 1H), 7.52 (d, J=9.1, 1H), 7.43 (s, 1H), 7.31 (d, J=8.7, 1H), 7.14(d, J=8.7, 1H), 6.84 (d, J=9.1, 1H), 4.27-4.24 (m, 2H), 3.51-3.48 (m,2H), 3.26 (s, 3H), 3.04-3.01 (m, 4H), 2.84 (s, 3H), 2.15 (s, 3H).

II-23:N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diaminetrifluoroacetate salt

¹H NMR (300 MHz, DMSO) δ 10.21 (s, 1H), 9.90 (s, 1H), 9.74 (s, 1H), 8.11(s, 1H), 7.84 (s, 1H), 7.61 (d, J=6.0, 2H), 7.26 (dd, J=8.8, 18.6, 2H),6.90 (d, J=9.0, 1H), 4.33 (d, J=10.3, 2H), 3.50 (d, J=8.6, 2H), 3.34 (s,3H), 3.08 (d, J=9.0, 4H), 2.85 (s, 3H), 2.14 (s, 3H).

II-24:N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.38 (s, 1H), 8.93 (s, 1H), 8.33 (d, J=2.5,1H), 8.03 (d, J=3.7, 1H), 7.68-7.66 (m, 2H), 7.30-7.22 (m, 2H), 6.74 (d,J=8.9, 1H), 3.37 (m, 4H), 3.24 (s, 3H), 2.55-2.49 (m, 7H).

II-25: Synthesis of6-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.97 (s, 1H), 9.49 (s, 1H), 8.15(s, 1H), 7.82 (s, 1H), 7.65 (d, J=11.7, 2H), 7.21 (d, J=8.8, 1H), 7.05(d, J=8.4, 1H), 6.89 (d, J=8.9, 1H), 4.34-4.31 (m, 4H), 3.09-3.07 (m,4H), 2.85 (s, 3H), 2.13 (s, 3H).

II-26:N4-(benzoxazolin-2-on-5-yl)-N2-[3-methyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 447 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.54 (s, 1H), 8.90(s, 1H), 8.34 (s, 1H), 8.17 (d, 1H, J=2.4 Hz), 7.86 (d, 1H, J=1.8 Hz),7.83 (s, 1H), 7.26 (m, 3H), 2.92 (s, 4H), 2.48 (s, 4H), 2.26 (s, 3H),2.07 (s, 3H), 1.99 (s, 3H).

II-27:N4-(benzimidazolin-2-on-5-yl)-N2-[3-methyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 446 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 10.51 (s, 1H), 10.49(s, 1H), 8.86 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.91 (d, 1H, J=7.5Hz), 7.78 (s, 1H), 7.06 (d, 2H, J=9.9 Hz), 6.86 (d, 1H, J=8.1 Hz), 4.10(q, 1H, J=5.1 Hz), 3.15 (d, 2H, J=3.9 Hz), 3.02 (s, 3H), 2.88 (s, 3H),2.51 (d, 2H, J=12.0 Hz), 2.06 (s, 3H), 1.92 (s, 3H).

II-28:N4-(benzoxazolin-2-on-5-yl)-N2-[3-methyl-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 459 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 8.75 (s, 1H), 8.30(s, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.26 (m, 2H), 7.18(d, 1H, J=8.4 Hz), 4.35 (s, 1H), 3.77 (br s, 2H), 3.50 (t, 2H, J=3.6Hz), 3.37 (m, 1H), 2.95 (m, 1H), 2.54 (s, 3H), 2.07 (s, 3H), 1.99 (s,3H), 1.82 (d, 1H, J=9.6 Hz).

II-29:N4-(benzoxazolin-2-on-5-yl)-N2-[3-methyl-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

LCMS (m/z): 463 (M+H).

II-30:N4-(benzoxazolin-2-on-5-yl)-N2-[3-methyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

LCMS (m/z): 451 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.55 (s, 1H), 8.91(s, 1H), 8.36 (s, 1H), 8.17 (d, 1H, J=3.8 Hz), 7.86 (d, 1H, J=1.8 Hz),7.83 (s, 1H), 7.26 (m, 3H), 2.92 (s, 4H), 2.48 (s, 4H), 2.26 (s, 3H),2.01 (s, 3H).

II-31:N4-(benzoxazolin-2-on-5-yl)-N2-[2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 445 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 8.54 (s, 1H), 8.21(s, 1H), 8.14 (d, 1H, J=1.8 Hz), 7.77 (s, 1H), 7.72 (dd, 1H, J=2.2 and8.8 Hz), 7.33 (d, 1H, J=8.4 Hz), 7.29 (s, 1H), 7.15 (d, 1H, J=8.4 Hz),6.36 (d, 1H, J=9.0 Hz), 4.48 (s, 1H), 3.52 (s, 1H), 3.38 (d, 1H, J=9.9Hz), 3.25 (d, 1H, J=9.6 Hz), 2.82 (d, 1H, J=9.6 Hz), 2.54 (s, 1H), 2.32(s, 3H), 2.06 (s, 3H), 1.89 (d, 1H, J=9.6 Hz), 1.76 (d, 1H, J=9.3 Hz).

II-32:N4-(benzoxazolin-2-on-5-yl)-N2-[2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 432 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.53 (s, 1H), 8.60(s, 1H), 8.23 (s, 1H), 8.17 (d, 1H, J=2.1 Hz), 7.78 (s, 1H), 7.75 (d,1H, J=2.4), 7.31 (m, 2H), 7.15 (d, 1H, J=8.4 Hz), 6.39 (d, 1H, J=8.7Hz), 4.68 (s, 1H), 3.59 (s, 1H), 3.73 (d, 1H, J=7.2 Hz), 3.60 (d, 1H,J=7.2 Hz), 3.38 (m, 1H), 3.14 (d, 1H, J=9.3 Hz), 2.05 (s, 3H), 1.88 (d,1H, J=9.9 Hz), 1.80 (d, 1H, J=9.9 Hz).

II-33:N4-(benzoxazolin-2-on-5-yl)-N2-[2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

LCMS (m/z): 448 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 9.28 (s, 1H), 8.84(s, 1H), 8.16 (d, 1H, J=1.8 Hz), 7.99 (d, 1H, J=3.6 Hz), 7.75 (dd, 1H,J=2.4 and 8.5 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.33 (s, 1H), 7.17 (d, 1H,J=8.7 Hz), 6.48 (d, 1H, J=8.7 Hz), 4.60 (s, 1H), 3.86 (s, 1H), 3.48 (d,1H, J=9.9 Hz), 3.38 (d, 1H, J=9.0 Hz), 2.96 (s, 2H), 2.52 (s, 3H), 2.04(d, 1H, J=9.6 Hz), 1.91 (d, 1H, J=9.9 Hz).

II-34:N4-(benzoxazolin-2-on-5-yl)-N2-[2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine

LCMS (m/z): 436 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.55 (s, 1H), 9.26(s, 1H), 8.83 (s, 1H), 8.15 (d, 1H, J=2.1 Hz), 7.99 (d, 1H, J=3.9 Hz),7.75 (dd, 1H, J=2.4 and 8.7 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.33 (s, 1H),7.15 (d, 1H, J=8.7 Hz), 6.45 (d, 1H, J=9.0 Hz), 4.71 (s, 1H), 4.59 (s,1H), 3.73 (d, 1H, J=6.9 Hz), 3.60 (d, 1H, J=7.2 Hz), 3.41 (d, 1H, J=9.9Hz), 3.16 (d, 1H, J=10.2 Hz), 1.88 (d, 1H, J=9.3 Hz), 1.81 (d, 1H,J=10.8 Hz).

II-35:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-[2-(1-methylpiperidin-4-yl)aminopyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS: purity: 99.48%; MS (m/e): 447.31 (M+H); ¹H NMR (300 MHz, DMSO) δ11.69 (s, 1H), 9.88 (br, 1H), 9.41 (br, 2H), 7.96 (s, 1H), 7.80 (s, 1H),7.53 (br, 1H), 7.21 (m, 3H), 6.60 (br, 1H), 3.77 (br, 1H), 3.47 (d,J=12.0, 2H), 3.00 (q, 2H), 2.79 (d, J=3.6, 3H), 2.12 (s, 3H), 2.08 (d,J=12.3, 2H), 1.60 (q, J=13.5, 2H).

II-36:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-[2-(1H-piperidin-4-yl)aminopyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS: purity: 99.62%; MS (m/e): 433.25 (M+H); ¹H NMR (300 MHz, DMSO) δ11.73 (s, 1H), 10.00 (s, 1H), 9.68 (s, 1H), 8.01 (s, 1H), 7.82 (br, 3H),7.55 (d, 1H), 7.21 (m, 2H), 7.15 (d, 1H), 6.88 (d, J=8.7, 1H), 4.24 (d,J=12.9, 2H), 3.27 (br, 1H), 2.86 (t, J=13.2, 2H), 2.12 (s, 3H), 1.90 (d,J=10.8, 2H), 1.40 (q, J=12.6, 2H).

II-37:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-[2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)aminopyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS: purity: 95.17%; MS (m/e): 473.37 (M+H); ¹H NMR (300 MHz, DMSO) δ11.67 (s, 1H), 9.81 (br, 1H), 9.37 (br, 2H), 7.98 (s, 1H), 7.78 (s, 1H),7.50 (br, 1H), 7.20 (s, 3H), 6.65 (d, 1H), 3.82 (br, 2H), 2.67 (d,J=4.5, 3H), 2.26 (m, 4H), 2.12 (m, 4H), 2.12 (s, 3H).

II-38:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(4-(8-methyl-2,8-diazabicyclo[3.2.1]octan-2-yl)phenyl)-5-methylpyrimidine-2,4-diamine

MS (ES) 459.06 (M+H); ¹H NMR (CD₃OD, 300 MHz) 8.33 (m, 2H), 8.17 (m,1H), 7.69-6.61 (m, 7H), 4.52 (m, 1H), 4.13 (m, 2H), 3.52 (m, 6H),2.40-2.18 (m, 4H), 2.15 (s, 3H).

II-39:N4-(benzo[d]oxazolin-2(3H)-on-5-yl)-N2-[3-trifluoromethyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 501 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 11.43 (s, 1H), 9.31(s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.39 (d, 1H, J=2.1 Hz), 7.89 (s,1H), 7.22 (m, 3H), 2.96 (t, 4H, J=4.8 Hz), 2.44 (br s, 4H), 2.22 (s,3H), 2.09 (s, 3H).

II-40:N4-(benzoxazolin-2-on-5-yl)-N2-[3-fluoro-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine

LCMS (m/z): 463 (M+H); ¹H NMR (DMSO d₆, 300 MHz): δ 9.03 (s, 1H), 8.40(s, 1H), 8.04 (s, 1H), 7.91 (d, 1H, J=15.9 Hz), 7.83 (s, 1H), 7.24 (m,3H), 4.56 (s, 1H), 4.00 (br s), 3.57 (m, 2H), 3.06 (br s, 2H), 2.64 (s,3H), 2.07 (s, 3H), 1.94 (d, 2H, J=9.0 Hz).

II-41:(S)-2-Methyl-4-{5-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridin-2-yl}-piperazine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO, 300 MHz): δ 8.71 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 8.18(s, 1H), 7.85-7.76 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.15 (m, 1H), 6.67(d, J=9.1, 1H), 3.89 (d, J=12.2, 2H), 2.52-2.38 (m, 2H), 2.21 (s, 3H),2.05 (s, 3H), 1.41 (s, 9H), 1.04 (d, J=6.0, 3H) ppm; MS (ES) 533 (M+H).

II-42:5-[5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.01 (s, 1H), 8.82 (d, J=5.5 Hz, 1H), 8.43 (s,1H), 8.34 (s, 1H), 7.70-7.89 (m, 2H), 7.43 (s, 1H), 7.10-7.28 (m, 2H),6.97 (s, 2H), 2.28 (s, 3H) ppm; MS (ES) 335 (M+H).

II-43:5-[2-(6-Methanesulfonyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.05 (s, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.49 (s,1H), 8.31 (s, 1H), 7.61-7.83 (m, 2H), 7.47 (s, 1H), 7.11-7.23 (m, 2H),6.91 (s, 1H), 3.15 (s, 3H), 2.22 (s, 3H) ppm; MS (ES) 413 (M+H).

II-44:5-{5-Methyl-2-[6-((S)-3-methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

MS (ES) 433 (M+H)

II-45:5-{5-Methyl-2-[6-(piperazine-1-carbonyl)-pyridin-3-ylamino]-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

MS (ES) 447 (M+H)

II-46:5-{2-[6-(4-Cyclopropylmethyl-piperazine-1-carbonyl)-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

MS (ES) 501 (M+H)

II-47:5-{2-[6-(4-Isobutyl-piperazine-1-carbonyl)-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

MS (ES) 503 (M+H)

II-48:5-{3-Fluoro-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridin-2-yl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

¹H NMR (DMSO, 300 MHz): δ 8.96 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 8.01(s, 1H), 7.89-7.94 (m, 1H), 7.83 (s, 1H), 7.14-7.33 (m, 3H), 3.14 (dd,J=11.0, 3.0 Hz, 4H), 2.87 (br. s., 4H), 2.48 (br. s., 2H), 2.06 (s, 3H),1.37 (s, 9H) ppm; MS (ES) 563 (M+H).

II-49:5-{3-Fluoro-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridin-2-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

¹H NMR (DMSO, 300 MHz): δ 9.03 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.03(br. s., 1H), 7.92 (d, J=15.7 Hz, 1H), 7.83 (s, 1H), 7.14-7.36 (m, 3H),4.59 (br. s., 1H), 4.36 (d, J=17.9 Hz, 1H), 2.40-2.57 (m, 4H), 2.06 (s,3H), 1.73-1.92 (m, 2H), 1.37 (s, 9H) ppm; MS (ES) 549 (M+H).

II-50:5-{2-[5-Fluoro-6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.93 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 8.02(s, 1H), 7.90-7.98 (m, 1H), 7.85 (s, 1H), 7.14-7.39 (m, 3H), 3.10 (dd,J=11.0, 3.0 Hz, 4H), 2.82 (br. s., 4H), 2.49 (br. s., 2H), 2.12 (s, 3H)ppm; MS (ES) 463 (M+H).

II-51:5-{2-[6-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

MS (ES) 449 (M+H)

II-52:5-{2-[6-(5-Cyclopropylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.05 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 8.06(s, 1H), 7.99-7.87 (m, 1H), 7.84 (s, 1H), 7.20 (s, 2H), 3.33 (s, 4H),3.16-2.98 (m, 2H), 2.94-2.74 (m, 2H), 2.70-2.54 (m, 2H), 2.50 (d, J=6.9,2H), 2.06 (s, 3H), 1.01-0.78 (m, 1H), 0.45 (s, 2H), 0.14 (s, 2H) ppm; MS(ES) 517 (M+H).

II-53:5-{2-[6-(5-Cyclopropanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 1.54 (s, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 8.11(s, 1H), 8.00 (s, 1H), 7.82 (s, 2H), 7.23 (d, J=10.8, 2H), 3.99-3.73 (m,2H), 3.56 (m, 5H), 3.12-2.77 (m, 3H), 2.06 (s, 3H), 1.82-1.64 (m, 1H),0.69 (s, 4H) ppm; MS (ES) 531 (M+H).

II-54:5-{2-[6-(5-Cyclopropylmethyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.11-8.81 (m, 1H), 8.60-8.30 (m, 1H), 8.18 (s,1H), 8.15-7.96 (m, 1H), 7.97-7.75 (m, 1H), 7.43-6.95 (m, 2H), 3.03-2.84(m, 1H), 2.91-2.64 (m, 2H), 2.46-2.32 (m, 2H), 2.06 (s, 3H), 1.95-1.62(m, 2H), 1.05-0.58 (m, 1H), 0.51-0.26 (m, 2H), 0.24-0.07 (m, 2H); ppm;MS (ES) 503 (M+H).

II-55:(R)-5-(2-(6-(3,4-dimethylpiperazin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₆N₈O₂. MS (ESI) m/z 447.57 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.71(s, 1H, NH), 8.27 (s, 1H, NH), 8.25 (s, 1H, NH), 8.18 (s, 1H, ArH),7.85-7.76 (m, 2H, ArH), 7.34-7.28 (m, 2H, ArH), 7.20-7.15 (m, 1H, ArH),6.67 (d, J=9.1, 1H, ArH), 3.89 (d, J=12.2, 2H, CH₂), 2.90-2.74 (m, 3H,CH, CH₂), 2.52-2.38 (m, 2H, CH₂), 2.21 (s, 3H, CH₃), 2.05 (s, 3H, CH₃),1.04 (d, J=6.0, 3H, CH₃).

II-56:(R)-5-(2-(6-(4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₆H₃₀N₈O₂. MS (ESI) m/z 487.62 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.69(s, 1H, NH), 8.26 (s, 1H, NH), 8.23 (s, 1H, NH), 8.19 (s, 1H, ArH),7.84-7.76 (m, 2H, ArH), 7.34-7.28 (m, 2H, ArH), 7.20-7.14 (m, 1H, ArH),6.67 (d, J=9.5, 1H, ArH), 3.79 (d, J=12.1, 2H, CH₂), 3.52 (d, J=13.3,2H, CH₂), 3.06-2.84 (m, 3H, CH, CH₂), 2.62-2.42 (m, 2H, CH₂), 2.21 (s,3H, CH₃), 2.08 (s, 3H, CH₃), 1.02 (d, J=5.5, 3H, CH₃), 0.89-0.78 (m, 1H,CH), 0.50-0.37 (m, 2H, CH₂), 0.12-0.02 (m, 2H, CH₂).

II-57:(R)-5-(5-methyl-2-(6-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₃F₃N₈O₃. MS (ESI) m/z 529.53 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.74(s, 1H, NH), 8.28 (s, 1H, ArH), 8.12 (s, 1H, NH), 7.85 (s, 1H, NH),7.84-7.77 (m, 2H, ArH), 7.35-7.28 (m, 2H, ArH), 7.19-7.16 (m, 1H, ArH),6.74-6.68 (m, 1H, ArH), 4.21-3.54 (m, 7H, CH, 3CH₂), 2.21 (s, 3H, CH₃),2.05 (s, 3H, CH₃), 1.20 (d, J=6.8, 3H, CH₃).

II-58: (R)-diethyl2-methyl-4-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)piperazin-1-ylphosphonate

C₂₆H₃₃N₈O₅P. MS (ESI) m/z 569.03 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 12.01(s, 1H, NH), 11.67 (s, 1H, NH), 8.15 (s, 1H, ArH), 7.79 (s, 1H, ArH),7.70-7.67 (m, 1H, ArH), 7.28-7.20 (m, 2H, ArH), 6.74-6.71 (m, 1H, ArH),6.61-6.54 (m, 1H, ArH), 3.96-3.54 (m, 11H, CH, 5CH₂), 2.48 (s, 3H, CH₃),2.08 (s, 3H, CH₃), 1.24-1.08 (m, 6H, 2CH₃).

II-59:5-(2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₂H₂₁F₂N₇O₂. MS (ESI) m/z 454.02 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.84(s, 1H, NH), 8.40 (s, 1H, NH), 8.27 (s, 1H, ArH), 8.11 (s, 1H, ArH),7.83-7.80 (m, 1H, ArH), 7.29-7.17 (m, 2H, ArH), 6.81 (d, J=9.1, 1H,ArH), 6.54 (s, 1H, ArH), 3.68-3.48 (m, 4H, 2CH₂), 2.06 (s, 3H, CH₃),1.98-1.87 (m, 4H, 2CH₂).

II-60:5-(2-(6-(4,4-dimethylpiperidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₇N₇O₂. MS (ESI) m/z 446.54 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.58(s, 1H, NH), 8.94 (s, 1H, NH), 8.59 (s, 1H, NH), 8.16 (s, 1H, ArH), 8.11(s, 1H, ArH), 7.78 (s, 1H, ArH), 7.27-7.17 (m, 2H, ArH), 6.71 (d, J=8.8,1H, ArH), 6.53 (s, 1H, ArH), 3.68-3.08 (m, 4H, 2CH₂), 2.06 (s, 3H, CH₃),1.47-1.18 (m, 4H, 2CH₂), 0.93 (s, 6H, 2CH₃).

II-61:5-(2-(6-(3,8-diaza-bicyclo[3.2.1]octan-3-yl)-5-methylpyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₄H₂₆N₈O₂. MS (ESI) m/z 459.09 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.01(s, 1H, NH), 8.36 (s, 1H, NH), 8.28 (s, 1H, ArH), 8.22 (s, 1H, NH), 7.90(s, 1H, ArH), 7.84 (s, 1H, ArH), 7.42-7.14 (m, 3H, ArH), 3.08-2.95 (m,6H, 2CH, 2CH₂), 2.06 (s, 3H, CH₃), 2.03 (s, 3H, CH₃), 1.90-1.86 (m, 4H,2CH₂).

II-62:5-(5-methyl-2-(5-methyl-6-(8-acetyl)-3,8-diaza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₆H₂₈N₈O₄. MS (ESI) m/z 516.82 (M+1)⁺.

II-63:5-(5-methyl-2-(5-methyl-6-(8-(2,2,2-trifluoroacetyl)-3,8-diaza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₆H₂₅F₃N₈O₃. MS (ESI) m/z 555.25 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.57(s, 1H, NH), 9.06 (s, 1H, NH), 8.49 (s, 1H, NH), 8.17 (s, 1H, ArH), 7.88(s, 1H, ArH), 7.84 (s, 1H, ArH), 7.31-7.16 (m, 3H, ArH), 3.65-3.38 (m,6H, 2CH, 2CH₂), 2.07 (s, 3H, CH₃), 2.05 (s, 3H, CH₃), 2.04-1.95 (m, 4H,2CH₂).

II-64:5-(5-methyl-2-(5-methyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₂₈N₈O₂. MS (ESI) m/z 473.19 (M+1)⁺.

II-65: tert-butyl3-(3-methyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

C₃₀H₃₅N₇O₄. MS (ESI) m/z 558.13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.57(s, 1H, NH), 9.02 (s, 1H, NH), 8.37 (s, 1H, ArH), 8.35 (s, 1H, NH), 7.89(s, 1H, ArH), 7.86 (s, 1H, ArH), 7.35-7.15 (m, 2H, ArH), 6.53 (s, 1H,ArH), 3.66-3.44 (m, 3H, 3CH), 2.07 (s, 3H, CH₃), 2.04 (s, 3H, CH₃),1.96-1.77 (m, 8H, 4CH₂), 1.40 (s, 9H, 3CH₃).

II-66:5-(2-(6-(8-aza-bicyclo[3.2.1]octan-3-yl)-5-methylpyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₂₇N₇O₂. MS (ESI) m/z 457.53 (M+1)⁺.

II-67:5-(2-(6-(8-(cyclopropylmethyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-methylpyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₉H₃₃N₇O₂. MS (ESI) m/z 512.16 (M+1)⁺.

II-68: methyl3-(3-methyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

C₂₇H₂₉N₇O₄. MS (ESI) m/z 516.16 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.07(s, 1H, NH), 8.45 (s, 1H, NH), 8.36 (s, 1H, NH), 8.26 (s, 1H, ArH), 7.91(s, 1H, ArH), 7.81 (s, 1H, ArH), 7.31-7.18 (m, 3H, ArH), 3.63 (s, 3H,CH₃), 3.45-3.20 (m, 3H, 3CH), 2.07 (s, 3H, CH₃), 2.05 (s, 3H, CH₃),2.23-1.97 (m, 8H, 4CH₂).

II-69:5-(5-methyl-2-(5-methyl-6-(8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₇H₂₆F₃N₇O₃. MS (ESI) m/z 554.14 (M+1)⁺.

II-70:(R)-5-(2-(6-(4-isopropyl-3-methylpiperazin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₅H₃₀N₈O₂. MS (ESI) m/z 475.09 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.68(s, 1H, NH), 8.26 (s, 1H, NH), 8.23 (s, 1H, NH), 8.17 (s, 1H, ArH), 7.79(s, br, 2H, ArH), 7.30 (s, br, 2H, ArH), 7.18-7.15 (m, 1H, ArH), 6.65(d, J=9.8, 1H, ArH), 3.91-3.80 (m, 1H, CH), 3.58-3.09 (m, 5H, CH, 2CH₂),2.81-2.70 (m, 2H, CH₂), 2.05 (s, 3H, CH₃), 1.04 (d, J=6.5, 6H, 2CH₃),0.83 (d, J=6.5, 3H, CH₃).

II-71:5-(5-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.97 (s, 1H), 9.51 (s, 1H),8.05-7.91 (m, 3H), 7.32-7.19 (m, 3H), 6.96 (br s, 1H), 3.48 (br t,J=6.1, 4H), 2.18 (s, 3H), 2.05 (br t, J=6.1, 4H); LRMS (M+) m/z 403.99.

II-72:7-methyl-5-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.25(s, 1H), 7.84-7.81 (m, 2H), 7.27 (s, 1H), 7.13 (s, 1H), 6.77 (d, J=9.3,1H), 3.37 (m, 4H, overlapped with H2O), 2.93 (s, 3H), 2.58-2.47 (m, 4H,overlapped with DMSO), 2.32 (s, 3H), 2.11 (s, 3H); LRMS (M+) m/z 447.11.

II-73:7-methyl-5-(5-methyl-2-(6-morpholinopyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 9.97 (s, 1H), 9.61 (s, 1H), 8.15(d, J=2.2, 1H), 7.82 (s, 1H), 7.59 (br d, J=8.6, 1H), 7.13 (s, 1H), 7.07(s, 1H), 6.86 (d, J=8.6, 1H), 3.74-3.71 (m, 4H), 3.45-3.42 (m, 4H), 2.30(s, 3H), 2.17 (s, 3H); LRMS (M+) m/z 434.07.

II-74:5-(2-(6-(cyclopropylmethylamino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.86 (s, 1H), 9.32 (s, 1H), 8.33(br s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.4, 1H), 7.32-7.29(m, 3H), 6.94 (d, J=8.4, 1H), 3.17 (br d, J=7.0, 2H), 2.17 (s, 3H),1.19-1.10 (m, 1H), 0.60-0.54 (m, 2H), 0.33-0.29 (m, 2H); LRMS (M+) m/z404.04.

II-75:7-fluoro-5-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.93 (br s, 1H), 8.93 (s, 1H), 8.42-8.37 (m,2H), 7.94-7.91 (m, 2H), 7.65 (d, J=13.6, 1H), 7.22 (s, 1H), 6.87 (d,J=9.3, 1H), 3.20-2.94 (m, 8H), 2.72 (br s, 3H), 2.12 (s, 3H); LRMS (M+)m/z 451.00.

II-76:7-fluoro-5-(5-methyl-2-(6-morpholinopyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 10.07 (s, 1H), 9.64 (s, 1H),8.15 (br s, 1H), 7.88 (s, 1H), 7.66 (br d, J=8.2, 1H), 7.43-7.40 (m,1H), 7.16 (s, 1H), 6.94 (d, J=9.4, 1H), 3.83-3.62 (m, 4H), 3.57-3.36 (m,4H), 2.18 (s, 3H); LRMS (M+) m/z 438.07.

II-77:5-(2-(5-bromopyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.86 (br s, 1H), 9.50 (s, 1H), 9.12 (s, 1H),8.92 (s, 1H), 8.44 (s, 1H), 8.01 (br s, 1H), 7.43-7.38 (m, 3H), 7.23 (brs, 1H), 2.37 (s, 3H); LRMS (M+) m/z 414.86.

II-78:N-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)methanesulfonamide

¹H NMR (300 MHz, DMSO) δ 9.06 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.00(d, J=8.9, 1H), 7.85 (s, 1H), 7.30 (s, 1H), 7.29 (d, J=8.9, 1H), 7.20(d, J=8.9, 1H), 6.80 (d, J=8.9, 1H), 3.19 (s, 3H), 2.08 (s, 3H).

II-79: N-(5-(5-methyl-4-(3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)methanesulfonamide

¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 7.91(d, J=8.9, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.25 (s, 2H), 6.79 (d,J=8.9, 1H), 3.28 (s, 3H), 3.17 (s, 3H), 2.10 (s, 3H).

II-80:5-(2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzooxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.79 (br s, 1H), 8.73 (br s,1H), 8.37 (br s, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 7.77 (d, J=8.2, 1H),7.31 (d, J=9.3, 2H), 7.29 (s, 1H), 7.17 (d, J=8.2, 1H), 6.42 (d, J=9.3,1H).

II-81: N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzooxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)acetamide

¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 9.75 (br s, 1H), 8.14 (s, 1H),8.02 (br s, 1H), 7.81 (br s, 2H), 7.26-7.22 (m, 4H), 6.84-6.62 (m, 1H),4.35 (dd, J=8.9, 4.5, 1H), 2.20-2.12 (m, 2H), 2.12 (s, 3H), 1.98-1.88(m, 2H), 1.82-1.77 (m, 2H), 1.81 (s, 3H).

II-82:5-(2-(6-(3-(diethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzooxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 9.61 (s, 1H), 9.15 (s, 1H), 8.09(s, 1H), 7.79 (s, 1H), 7.65 (d, J=8.7, 1H), 7.23 (d, J=12.1, 2H), 7.21(s, 1H), 6.50 (d, J=8.7, 1H), 4.08 (dd, J=14.8, 7.2, 1H), 3.84 (t,J=9.1, 1H), 3.60 (t, J=9.1, 1H), 3.47-3.16 (m, 4H), 2.53-2.37 (m, 2H),2.22-2.04 (m, 2H), 2.10 (s, 3H), 1.24 (t, J=7.0, 6H).

II-83: 2,2,2-trifluoro-N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzooxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)acetamide

¹H NMR (300 MHz, DMSO) δ 9.68 (br s, 1H), 8.53 (s, 1H), 8.16 (s, 1H),8.09 (s, 1H), 7.80 (d, J=8.9, 1H), 7.75 (s, 1H), 7.21 (d, J=8.5, 1H),7.20 (s, 1H), 7.03 (d, J=8.5, 1H), 6.32 (d, J=8.9, 1H), 4.43 (br s, 1H),3.62 (dd, J=10.8, 6.5, 1H), 3.45 (dd, J=10.8, 6.5, 1H), 2.22 (dd,J=12.9, 7.0, 2H), 2.05 (s, 3H), 2.06-1.93 (m, 2H).

II-84:5-(5-methyl-2-(6-(3-morpholinopyrrolidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-85:5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.49 (s, 1H), 9.37 (s, 1H), 8.60 (s, 1H), 8.28(s, 1H), 8.20 (s, 1H), 7.67 (d, J=8.7, 1H), 7.22 (d, J=8.5, 1H), 7.11(s, 1H), 7.09 (d, J=8.5, 2H), 6.71 (d, J=8.7, 1H), 4.20 (br s, 2H), 3.48(br s, 2H), 3.05 (br s, 4H), 2.85 (s, 3H).

II-86: tert-butyl1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate

¹H NMR (300 MHz, DMSO) δ 8.51 (d, J=9.2, 1H), 8.14 (s, 2H), 7.75 (s,2H), 7.26 (s, 2H), 7.09-7.03 (m, 1H), 6.27 (d, J=8.7, 1H), 4.16-3.93 (m,−1H), 2.07-1.99 (m, 5H), 1.85 (dd, J=12.1, 7.1, 2H), 1.38 (s, 9H).

II-87: (S)-tert-butylmethyl(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)piperidin-3-yl)carbamate

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.95 (s, 1H), 9.65 (s, 1H), 8.00(s, 1H), 7.77 (s, 1H), 7.57 (d, J=7.8, 1H), 7.21 (d, J=7.3, 2H), 7.20(s, 1H), 6.88 (d, J=7.8, 1H), 4.14 (t, J=11.2, 2H), 2.88 (t, J=12.2,1H), 2.75 (s, 3H), 2.74 (d, J=12.2, 1H), 2.63 (t, J=5.6, 1H), 2.13 (s,3H), 1.74 (br t, J=10.5, 4H), 1.39 (s, 9H).

II-88:(R)-5-(5-methyl-2-(6-(3-(methylamino)piperidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 8.55 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.81(d, J=8.9, 1H), 7.74 (s, 1H), 7.14 (s, 1H), 7.10 (d, J=8.5, 1H), 6.96(d, J=8.5, 1H), 6.63 (d, J=8.9, 1H), 4.09 (d, J=11.6, 1H), 3.89 (d,J=11.6, 1H), 2.79-2.69 (m, 1H), 2.54-2.47 (m, 1H), 2.31 (s, 3H), 2.05(s, 3H), 1.89 (d, J=13.6, 1H), 1.67 (d, J=13.6, 1H), 1.42 (d, J=13.6,1H), 1.25-1.13 (m, 2H).

II-89:(R)-5-(2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-90:(S)-5-(2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-91: (R)-tert-butylmethyl(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)piperidin-3-yl)carbamate

¹H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.84(d, J=9.1, 1H), 7.78 (s, 1H), 7.26 (d, J=8.5, 1H), 7.23 (s, 1H), 7.09(d, J=8.5, 1H), 6.67 (d, J=9.1, 1H), 4.09-3.99 (m, 2H), 2.73 (s, 3H),2.61-2.39 (m, 3H), 2.04 (s, 3H), 1.71 (d, J=12.4, 3H), 1.38 (app s,10H).

II-92:(R)-5-(5-methyl-2-(6-(3-(methylamino)piperidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 8.73 (s, 1H), 8.28 (app s, 2H), 7.84 (d, J=9.2,1H), 7.80 (s, 1H), 7.34 (d, J=8.6, 1H), 7.31 (s, 1H), 7.18 (d, J=8.6,1H), 6.75 (d, J=9.2, 1H), 4.02 (d, J=10.4, 1H), 3.62 (d, J=10.4, 1H),3.16-3.02 (m, 3H), 2.58 (s, 3H), 2.05 (s, 3H), 1.97 (d, J=11.0, 1H),1.74 (d, J=11.5, 2H), 1.52 (dd, J=17.1, 8.8, 2H).

II-93: N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzooxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)methanesulfonamideII-94:5-(2-(6-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-95:(S)-5-(2-(6-((1-benzylpiperidin-3-yl)(methyl)amino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-96:1-ethyl-3-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)ureaII-97:1-tert-butyl-3-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)ureaII-98:1-benzyl-3-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)ureaII-99:(S)-5-(2-(6-(1-benzylpiperidin-3-ylamino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-100:(S)-5-(2-(6-((1-benzylpiperidin-3-yl)(methyl)amino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-101:N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)cyclopropanecarboxamideII-102:N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)pivalamideII-103:(S)-5-(5-methyl-2-(6-(methyl(piperidin-3-yl)amino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-104:(S)-5-(5-methyl-2-(6-(piperidin-3-ylamino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-105:(S)-5-(2-(6-(1-benzylpiperidin-3-ylamino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-106:(R)-5-(2-(6-((1-benzylpiperidin-3-yl)(methyl)amino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-107:(R)-5-(5-methyl-2-(6-(piperidin-3-ylamino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-108:(R)-5-(5-methyl-2-(6-(methyl(piperidin-3-yl)amino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-109:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-5-methyl-N2-[2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-trifluoromethylpyridine-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 8.99 (s, 1H), 8.51 (s, 1H), 8.34 (s, 1H),8.20 (s, 1H), 7.84 (s, 1H), 7.23 (m, 2H), 7.15 (d, 1H, J=8.7 Hz), 4.46(s, 1H), 3.48 (br, 1H), 3.42 (d, 1H, J=9.6 Hz), 3.30 (d, 1H, J=9.3 Hz),2.79 (s, 2H), 2.32 (s, 3H), 2.08 (s, 3H), 1.84 (d, 1H, J=10.2 Hz), 1.68(d, 1H, J=8.7 Hz); LCMS (m/z): 513 (M+H).

II-110:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[2-(4-ethylpiperazin-1-yl)-3-trifluoromethylpyridine-5-yl]-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.45 (s, 1H), 9.33 (s, 1H), 8.68 (s, 1H),8.43 (s, 1H), 8.40 (d, 1H), 7.89 (s, 1H), 7.24 (s, 1H), 7.19 (m, 2H),3.00 (t, 4H), 2.10 (s, 3H), 1.05 (t, 3H, J=6.6 Hz); LCMS (m/z): 515(M+H).

II-111:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[3-fluoro-2-(4-methylpiperazin-1-yl)pyridine-5-yl]-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.52 (br, 1H), 9.10 (s, 1H), 8.40 (s, 1H),8.10 (s, 1H), 7.96 (d, 1H, J=15.9 Hz), 7.85 (s, 1H), 7.21 (m, 3H), 3.19(t, 4H), 2.49 (s, 4H), 2.24 (s, 3H), 2.08 (s, 3H); LCMS (m/z): 451(M+H).

II-112:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-{2-[(8S)-1,4-diazabicyclo[4.3.0]nonane-1-yl]-3-fluoropyridine-5-yl}-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.51 (br, 1H), 9.09 (s, 1H), 8.40 (s, 1H),8.09 (s, 1H), 7.95 (dd, 1H, J=15.9 Hz), 7.85 (s, 1H), 7.21 (m, 3H), 3.73(d, 1H, J=11.1 Hz), 3.61 (d, 1H, J=12.6 Hz), 2.99 (d, 2H, J=8.7 Hz),2.84 (t, 1H, J=11.4 Hz), 2.54 (br, 1H), 2.08 (m, 6H), 1.68 (m, 2H), 1.34(m, 2H); LCMS (m/z): 477 (M+H).

II-113:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-{2-[(8R)-1,4-diazabicyclo[4.3.0]nonane-1-yl]-3-fluoropyridine-5-yl}-5-methyl-2,4-pyrimidinediamine

LCMS (m/z): 477 (M+H).

II-114:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[2-(4-ethylpiperazin-1-yl)-3-fluoropyridine-5-yl]-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.67 (s, 1H), 10.18 (br, 1H), 9.50 (br,2H), 8.04 (s, 1H), 7.89 (s, 1H), 7.76 (d, 1H, J=13.2 Hz), 7.26 (d, 1H,J=8.4 Hz), 7.18 (m, 2H), 3.87 (d, 2H, J=9.6 Hz), 3.54 (d, 2H, J=8.1 Hz),3.20-3.09 (m, 6H), 2.13 (s, 3H), 1.24 (t, 3H, J=7.5 Hz); ¹⁹F NMR (DMSOd₆, 282 MHz): δ −143.33; LCMS (m/z): 465 (M+H).

II-115:N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[3-cyano-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridine-5-yl]-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.60 (s, 1H), 9.86 (br, 1H), 9.45 (br,2H), 8.34 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.25 (d, 1H, J=8.7 Hz),7.15 (m, 2H), 4.90 (s, 1H), 4.36 (s, 1H), 3.92 (d, 1H, J=12.9 Hz), 3.72(d, 1H, J=11.1 Hz), 3.70 (m, 1H), 3.15 (d, 1H), 2.87 (d, 3H, J=4.8 Hz),2.12 (s, 5H); LCMS (m/z): 470 (M+H).

II-116:N2-[3-chloro-2-(4-methylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.17 (s, 1H), 8.43 (s, 1H), 8.25 (d, 1H), 8.21(m, 2H), 7.86 (s, 1H), 7.20 (m, 3H), 3.05 (br, 4H), 2.42 (sbr, 4H), 2.20(s, 3H), 2.08 (s, 3H); LCMS: purity: 94.13%; MS (m/e): 467.23 (M+H).

II-117:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[2-(1,3,5-trimethyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)pyridin-5-yl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 10.01 (br, 1H), 9.66 (br, 1H),8.50 (br, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 7.65 (d, 1H), 7.26 (d, J=9.0,2H), 7.09 (d, 1H), 6.97 (d, J=9.6, 1H), 3.96 (d, J=12.0, 2H), 3.38 (d,J=12.9, 2H), 2.83 (t, 2H), 2.66 (d, J=4.5, 3H), 2.13 (s, 3H), 1.48 (q,J=14.0, 2H), 1.00 (s, 8H); LCMS: purity: 91.39%; MS (m/e): 501.38 (M+H).

II-118:N2-[3-chloro-2-(3-ethyl-3,7-diazabicyclo[3.3.0]octan-7-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.95 (br, 1H), 9.60 (br, 1H),9.45 (br, 1H), 8.11 (s, 1H), 7.86 (m, 2H), 7.24 (d, 1H), 7.14 (m, 2H),3.88 (br, 2H), 3.58 (d, J=11.1, 2H), 3.41 (m, 2H), 3.21 (t, 2H), 3.13(t, 2H), 2.96 (m, 1H), 2.74 (m, 1H), 2.12 (s, 3H), 1.21 (t, J=6.9, 3H);LCMS: purity: 94.05%; MS (m/e): 507.33 (M+H).

II-119:N2-[2-(3-ethyl-3,7-diazabicyclo[3.3.0]octan-7-yl)-3-trifluoromethylpyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.98 (br, 1H), 9.72 (br, 1H),9.53 (br, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.18 (m, 3H),3.89 (br, 2H), 3.38-3.15 (m, 6H), 2.98 (m, 2H), 2.69 (m, 2H), 2.12 (s,3H), 1.21 (t, J=7.2, 3H); LCMS: purity: 88.57%; MS (m/e): 541.37 (M+H).

II-120:5-methyl-N2-[2-(3-methyl-3,7-diazabicyclo[3.3.0]octan-7-yl)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.84 (br, 2H), 8.02 (s, 1H),7.80 (s, 1H), 7.60 (br, 1H), 7.21 (m, 3H), 6.61 (br, 1H), 3.85 (br, 2H),3.58-3.44 (m, 4H), 3.30 (br, 2H), 3.08 (s, 2H), 2.82 (m, 3H), 2.12 (s,3H); LCMS: purity: 95.06%; MS (m/e): 459.33 (M+H).

II-121:5-methyl-N2-[2-(octahydroisoindol-1-yl)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 9.71 (br, 1H), 8.05 (br, 1H),7.83 (s, 2H), 7.26 (s, 1H), 7.22 (m, 2H), 6.84 (br, 1H), 3.44 (m, 2H),3.31 (m, 2H), 2.36 (s, 2H), 2.12 (s, 3H), 1.59 (m, 2H), 1.39 (m, 6H);LCMS: purity: 92.74%; MS (m/e): 458.30 (M+H).

II-122:N2-[3-chloro-2-(octahydroisoindol-1-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.49 (br, 1H), 8.89 (s, 1H), 8.34 (s, 1H),8.11 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.21 (s, 2H), 7.17 (d, J=9.3,1H), 3.46 (m, 2H), 3.40 (m, 2H), 2.17 (s, 2H), 2.07 (s, 3H), 1.52 (m,4H), 1.35 (m, 4H); LCMS: purity: 84.77%; MS (m/e): 492.27 (M+H).

II-123:N2-(2-methoxypyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.98 (s, 1H), 9.62 (s, 1H), 8.08(d, J=2.7, 1H), 7.81 (s, 1H), 7.71 (dd, J=9.0, 2.7, 1H), 7.24 (d, J=8.4,1H), 7.18 (s, 1H), 7.16 (d, J=8.7, 1H), 6.75 (d, J=9.0, 1H), 3.79 (s,3H), 2.13 (s, 3H); LCMS: purity: 97.58%; MS (m/e): 365.23 (M+H).

II-124:N2-[2-(S-1,4-diazabicylco[4.3.0]nonan-4-yl)-3-trifluoromethylpyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 10.06 (br, 1H), 9.94 (br, 1H),9.61 (br, 1H), 9.08 (br, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.92 (s, 1H),7.19 (m, 3H), 3.82 (m, 1H), 3.65 (m, 2H), 3.44 (m, 2H), 3.24 (m, 2H),3.10 (m, 2H), 2.12 (s, 3H), 2.03 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ−76.17; LCMS: purity: 97.06%; MS (m/e): 527.32 (M+H).

II-125:N2-[2-(1,4-diazabicylco[3.2.2]nonan-4-yl)-3-fluoropyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 10.14 (s, 2H), 9.61 (br, 1H),7.97 (s, 1H), 7.87 (s, 1H), 7.65 (d, J=14.1, 1H), 7.26 (d, J=8.4, 1H),7.17 (s, 1H), 7.13 (d, J=8.7, 1H), 4.19 (s, 1H), 3.76 (t, J=5.1, 2H),3.46 (s, 2H), 3.38 (t, 4H), 2.13 (s, 3H), 2.06 (m, 4H); ¹⁹F NMR (282MHz, DMSO) δ −144.17; LCMS: purity: 97.39%; MS (m/e): 477.30 (M+H).

II-126:N2-[2-(4R-hydroxy-2-methylidene-pyrrolidin-1-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.44 (s, 1H), 8.69 (s, 1H), 8.32 (s, 1H), 7.95(d, J=7.2, 1H), 7.80 (s, 1H), 7.20 (d, J=9.0, 1H), 6.83 (s, 1H), 5.24(m, 1H), 4.40 (m, 3H), 4.22 (m, 1H), 3.56 (m, 1H), 2.06 (s, 3H), 1.95(m, 1H), 1.79 (m, 1H); LCMS: purity: 87.05%; MS (m/e): 432.35 (M+H).

II-127:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[2-(cis-3,4,5-trimethylpiperazino)pyridin-5-yl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 10.01 (br, 1H), 9.69 (br, 1H),9.32 (br, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.60 (d, J=8.4, 1H), 7.24 (d,J=8.7, 1H), 7.20 (s, 1H), 7.14 (d, 1H), 6.95 (d, J=9.6, 1H), 4.37 (d,J=12.6, 2H), 3.29 (br, 2H), 2.85 (d, J=4.8, 3H), 2.13 (s, 3H), 1.37 (d,J=6.3, 6H); LCMS: purity: 93.68%; MS (m/e): 461.33 (M+H).

II-128:N2-[2-(1,4-diazabicylco[4.4.0]decan-4-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.07 (s, 1H), 9.71 (s, 1H),9.56 (br, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.61 (d, J=9.0, 1H), 7.24 (d,J=8.7, 1H), 7.20 (s, 1H), 7.14 (d, J=8.1, 1H), 6.92 (d, J=9.0, 1H), 4.35(m, 2H), 3.45 (t, J=11.7, 2H), 3.05 (m, 4H), 2.81 (t, J=12.6, 1H), 2.13(s, 3H), 1.82 (m, 4H), 1.49 (t, 2H); LCMS: purity: 95.73%; MS (m/e):473.33 (M+H).

II-129:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[2-(trans-2,4,5-trimethylpiperazino)pyridin-5-yl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.93 (br, 1H), 9.74 (br, 2H),8.03 (s, 1H), 7.80 (d, 1H), 7.58 (d, J=7.5, 1H), 7.18 (m, 3H), 6.83 (d,J=8.4, 1H), 4.66 (m, 1H), 4.19 (d, J=14.7, 1H), 3.66 (m, 1H), 3.26 (m,2H), 2.86 (d, 1H), 2.78 (d, 3H), 2.13 (s, 3H), 1.22 (d, J=6.6, 3H), 1.16(d, J=6.6, 3H); LCMS: purity: 91.43%; MS (m/e): 461.38 (M+H).

II-130:N2-[2-(trans-2,5-dimethylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.07 (s, 1H), 9.71 (s, 1H),8.82 (br, 2H), 8.04 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=9.9, 1H), 7.22 (d,J=8.7, 1H), 7.18 (s, 1H), 7.14 (d, J=9.0, 1H), 6.82 (d, J=9.3, 1H), 4.46(s, 1H), 3.89 (d, J=13.8, 1H), 3.66 (s, 1H), 3.30 (br, 1H), 3.28 (d,J=14.1, 1H), 3.08 (d, J=11.4, 1H), 2.13 (s, 3H), 1.26 (d, J=6.3, 3H),1.13 (d, J=6.6, 3H); LCMS: purity: 94.96%; MS (m/e): 447.31 (M+H).

II-131:N2-[2-(cis-3,5-dimethylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.85 (br, 1H), 9.44 (br, 1H),9.00 (d, 1H), 8.46 (d, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.64 (d, J=8.1,1H), 7.22 (m, 2H), 7.15 (d, J=8.4, 1H), 6.90 (d, J=9.6, 1H), 4.33 (d,J=11.7, 2H), 3.27 (m, 2H), 2.68 (t, J=12.3, 2H), 2.12 (s, 3H), 1.27 (d,J=6.6, 6H); LCMS: purity: 96.91%; MS (m/e): 447.18 (M+H).

II-132:N2-[2-(R-1,4-diazabicylco[4.3.0]nonan-4-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.99 (s, 1H), 8.22 (s, 1H), 7.80(s, 2H), 7.24 (m, 3H), 6.87 (m, 1H), 4.56 (m, 1H), 4.40 (m, 1H), 3.80(m, 5H), 3.01 (m, 2H), 2.10 (s, 3H), 2.00 (m, 4H); LCMS: purity: 95.82%;MS (m/e): 459.25 (M+H).

II-133:5-methyl-N2-[2-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 9.90 (br, 1H), 8.02 (br, 1H),7.77 (s, 1H), 7.21 (s, 3H), 6.47 (br, 1H), 3.56 (m, 4H), 3.15 (m, 4H),2.87 (s, 3H), 2.11 (s, 3H), 1.99 (m, 4H); LCMS: purity: 95.44%; MS(m/e): 473.27 (M+H).

II-134:5-methyl-N2-[2-(3S-methylmorpholino)pyridin-5-yl]-N-4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.67 (s, 1H), 8.25 (d, J=4.5,2H), 7.80 (d, J=9.6, 1H), 7.78 (s, 1H), 7.32 (d, J=10.5, 1H), 7.28 (s,1H), 7.16 (d, J=8.7, 1H), 6.60 (d, J=9.0, 1H), 4.16 (d, 1H), 3.88 (d,J=7.8, 1H), 3.63 (q, J=10.2, 3H), 3.46 (t, J=10.2, 1H), 2.94 (t, J=12.3,1H), 2.06 (s, 3H), 1.03 (d, J=6.6, 3H); LCMS: purity: 95.68%; MS (m/e):434.10 (M+H).

II-135:5-methyl-N2-[2-(2R-methylmorpholino)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 8.25(s, 1H), 7.80 (d, J=9.6, 1H), 7.79 (s, 1H), 7.30 (d, J=9.3, 1H), 7.29(s, 1H), 7.17 (d, J=8.7, 1H), 6.67 (d, J=8.4, 1H), 3.94 (d, J=12.3, 1H),3.85 (t, J=11.4, 2H), 3.54 (t, J=10.5, 2H), 2.67 (t, J=12.3, 1H), 2.34(t, J=11.1, 1H), 2.06 (s, 3H), 1.14 (d, J=5.7, 3H); LCMS: purity:80.08%; MS (m/e): 434.10 (M+H).

II-136:N2-[2-(4-isopropylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 8.23 (s, 2H), 7.80 (d, J=10.8,1H), 7.78 (s, 1H), 7.29 (d, J=10.8, 1H), 7.27 (s, 1H), 7.14 (d, J=8.4,1H), 6.64 (d, J=9.3, 1H), 4.08 (br, 4H), 2.64 (p, J=6.0, 1H), 2.06 (s,3H), 0.98 (d, J=6.6, 6H); LCMS: purity: 93.75%; MS (m/e): 461.32 (M+H).

II-137:N2-[2-(3-N,N-dimethylamino-8-azabicyclo[3.2.1]octan-8-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 10.00 (br, 1H), 9.70 (br, 1H),9.12 (br, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H), 7.26 (d, J=8.4,1H), 7.22 (s, 1H), 7.13 (d, J=9.3, 1H), 6.89 (d, 1H), 4.58 (s, 2H), 3.63(s, 1H), 2.65 (d, J=3.9, 6H), 2.13 (s, 3H), 1.94 (m, 4H), 1.78 (d,J=7.8, 2H), 1.56 (t, 2H); LCMS: purity: 93.35%; MS (m/e): 487.36 (M+H).

II-138:5-methyl-N2-[2-(2S-methylmorpholino)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.25(s, 1H), 7.79 (m, 2H), 7.28 (m, 2H), 7.17 (d, J=8.7, 1H), 6.67 (d,J=9.0, 1H), 3.94 (d, J=12.0, 1H), 3.86 (t, J=11.4, 2H), 3.54 (t, J=10.2,2H), 2.67 (t, J=12.0, 1H), 2.35 (t, J=11.1, 1H), 2.07 (s, 3H), 1.14 (d,J=6.0, 3H); LCMS: purity: 94.46%; MS (m/e): 434.20 (M+H).

II-139:5-methyl-N2-{2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridin-5-yl}-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 8.96 (br, 1H), 8.65 (br, 1H),8.12 (d, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 7.27 (s, 2H), 7.17 (d, J=9.0,1H), 6.48 (d, 1H), 4.72 (s, 1H), 4.61 (s, 1H), 3.74 (d, J=7.5, 1H), 3.60(d, J=7.5, 1H), 3.41 (d, J=9.6, 1H), 3.17 (d, J=9.6, 1H), 2.07 (s, 3H),1.86 (q, J=9.3, 2H); LCMS: purity: 96.51%; MS (m/e): 432.22 (M+H).

II-140:N2-(2,3-dimethoxypyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.50 (br, 2H), 7.75 (s, 1H),7.42 (s, 1H), 7.27 (d, 1H), 7.23 (s, 2H), 6.80 (s, 1H), 3.59 (s, 3H),3.30 (s, 3H), 2.13 (s, 3H); LCMS: purity: 87.99%; MS (m/e): 395.21(M+H).

II-141:N2-(2-methoxy-3-methylpyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.55 (s, 1H), 8.30 (s, 1H), 7.80 (s, 2H), 7.35(s, 1H), 7.27 (d, J=9.6, 1H), 7.26 (s, 1H), 7.18 (d, J=8.7, 1H), 3.17(s, 3H), 2.06 (s, 3H), 1.92 (s, 3H); LCMS: purity: 90.12%; MS (m/e):379.18 (M+H).

II-142:N2-[2-(2-hydroxy)ethoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.87 (s, 1H), 8.31 (s, 1H), 8.26(s, 1H), 7.96 (d, J=9.3, 1H), 7.82 (s, 1H), 7.29 (s, 2H), 7.18 (d,J=8.4, 1H), 6.62 (d, J=8.4, 1H), 4.78 (t, 1H), 4.15 (t, J=5.1, 2H), 3.66(q, J=4.8, 2H), 2.07 (s, 3H); LCMS: purity: 95.34%; MS (m/e): 395.19(M+H).

II-143:N2-[4-methyl-2-(4-methylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.68 (br, 1H), 9.63 (br, 2H), 8.00 (s, 1H),7.73 (br, 1H), 7.16 (br, 2H), 6.89 (s, 1H), 4.36 (d, J=9.0, 2H), 3.52(d, 2H), 3.03 (d, 4H), 2.84 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H); LCMS:purity: 90.64%; MS (m/e): 447.27 (M+H).

II-144:N2-(2-isopropoxypyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.10 (s, 1H), 9.76 (s, 1H),8.05 (d, J=2.7, 1H), 7.82 (s, 1H), 7.66 (dd, J=9.0, 2.7, 1H), 7.25 (d,J=8.1, 1H), 7.15 (d, J=12.0, 2H), 6.69 (d, J=9.3, 1H), 5.13 (p, J=6.0,1H), 2.13 (s, 3H), 1.24 (d, J=6.3, 6H); LCMS: purity: 100%; MS (m/e):393.04 (M+H).

II-145:N2-[2-(2-methoxy)ethoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 8.87 (s, 1H), 8.30 (d, J=6.9,2H), 7.96 (d, J=7.8, 1H), 7.83 (s, 1H), 7.30 (d, J=7.5, 2H), 7.19 (d,J=8.4, 1H), 6.63 (d, J=8.4, 1H), 4.26 (t, J=4.2, 2H), 3.60 (t, J=4.5,2H), 3.26 (s, 3H), 2.06 (s, 3H); LCMS: purity: 85.13%; MS (m/e): 409.26(M+H).

II-146:N2-[2-(1-aminocarbonyl-1-methyl)ethoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 98.61%; MS (m/e): 436.25 (M+H).

II-147:N2-(2-methoxy-3-trifluoromethylpyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.93%; MS (m/e): 433.22 (M+H).

II-148:N2-[2-(3-hydroxy)propoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 85.08%; MS (m/e): 409.29 (M+H).

II-149:N2-[2-(3-methoxy)propoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 98.76%; MS (m/e): 423.22 (M+H).

II-150:5-(2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-chloropyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneII-151:5-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridine-2-carboxylicacid cyclobutylamide

¹H NMR (DMSO, 300 MHz): δ 9.61 (s, 1H), 8.77 (s, 1H), 8.57 (d, J=8.6,1H), 8.49 (s, 1H), 8.39 (d, J=8.6, 1H), 8.33 (d, J=11.1, 1H), 7.91 (d,J=9.1, 1H), 7.76 (d, J=8.7, 1H), 7.66 (d, J=8.5, 1H), 7.41 (s, 1H), 7.25(s, 1H), 6.95 (d, J=8.5, 1H), 4.39 (dt, J=8.5, 16.9, 2H), 2.08 (s, 3H),1.60 (m, 5H) ppm; MS (ES) 432 (M+H);

II-152:N2-(5-methoxypyridin-3-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.38 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.38(s, 1H), 7.32 (m, 4H), 6.85 (s, 2H), 3.91 (s, 3H), 2.29 (s, 3H); LCMS:purity: 100%; MS (m/e): 365.37 (MH+).

II-153:N2-(2,3-dimethylpyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.24 (br, 1H), 9.00 (s, 1H), 8.36 (s, 1H),8.31 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.28 (d, J=7.5, 1H), 7.27 (s,1H), 7.21 (d, J=9.3, 1H), 2.26 (s, 3H), 2.07 (s, 3H), 1.96 (s, 3H);LCMS: purity: 97.66%; MS (m/e): 363.37 (MH+).

III-1:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(isoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 375.23 (M+H); ¹H NMR (300 MHz, DMSO) δ 9.06-8.84 (m, 1H),8.46-8.21 (m, 1H), 7.94-7.75 (m, 2H), 7.74-7.49 (m, 2H), 7.49-7.26 (m,2H), 7.27-6.92 (m, 2H), 3.88 (m, 4H), 2.07 (s, 3H) ppm.

III-2:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-hydroxyisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 391.38 (M+H), 389.37 (M−H);

III-3:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-tert-butoxoxycarbonylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 475.06 (M+H), 473.20 (M−H); ¹H NMR (300 MHz, DMSO) δ 9.01-8.81(m, 1H), 8.37-8.21 (m, 1H), 7.75 (m, 2H), 7.54 (m, 2H), 7.29 (m, 2H),7.18-6.98 (m, 2H), 3.78 (m, 4H), 2.11 (s, 3H), 1.51 (s, 9H) ppm.

III-4:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-methylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 389.08 (M+H), 3387.18 (M−H).

III-5:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-ethylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 403.15 (M+H), 401.77 (M−H).

III-6:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-n-propylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 417.50 (M+H), 415.45 (M−H).

III-7:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-cyclopropylmethylylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 429.11 (M+H), 427.23 (M−H).

III-8:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-isobutylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 431.15 (M+H), 429.12 (M−H).

III-9:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-isopentylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 445.10 (M+H), 443.24 (M−H).

III-10:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-cyclopentylmethylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 457.12 (M+H), 455.24 (M−H).

III-11:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(2-(bicyclo[2.2.1]heptan-2-ylmethyl)isoindolin-5-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 481.10 (M+H), 479.26 (M−H).

III-12:5-[2-(2-Acetyl-2,3-dihydro-1H-isoindol-5-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.94-9.12 (m, 1H), 8.24-8.45 (m, 1H), 8.14 (s,1H), 7.87 (br. s., 1H), 7.65-7.81 (m, 1H), 7.47-7.62 (m, 1H), 7.19-7.37(m, 3H), 7.09 (t, J=6.7 Hz, 1H), 4.36-4.92 (m, 4H), 1.97-2.13 (m, 6H)ppm; MS (ES) 417 (M+H).

III-13:N-{2-[2-(2,2-Dimethyl-propionyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-methyl-pyrimidin-4-yl}-N-[3-(2,2-dimethyl-propionyl)-2-oxo-2,3-dihydro-benzooxazol-5-yl]-2,2-dimethyl-propionamide

MS (ES) 627 (M+H)

III-14:5-[2-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-5-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

MS (ES) 453 (M+H)

IV-1:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 471.16 (M+H), 469.26 (M−H); ¹H NMR (300 MHz, DMSO) δ 11.87 (s,1H), 10.58 (s, 1H), 9.87-9.62 (m, 1H), 7.92 (s, 2H), 7.29 (s, 2H), 7.22(s, 2H), 7.01 (s, 1H), 3.52-3.26 (m, 1H), 3.21-2.93 (m, 4H), 2.81-2.53(m, 2H), 2.44-2.17 (m, 2H), 2.12 (s, 3H), 2.05-1.65 (m, 4H), 1.41-1.11(m, 4H) ppm.

IV-2:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-on-3-yl)-5-methylpyrimidine-2,4-diamine

MS (ES) 416.08 (M+H), 414.16 (M−H); ¹H NMR (300 MHz, DMSO) δ 11.70 (s,1H), 10.57 (s, 1H), 9.81 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.56 (s,1H), 7.45 (d, J=8.2, 1H), 7.35-6.99 (m, 3H), 2.86 (m, 2H), 2.59 (m, 2H),2.13 (s, 3H), 1.65 (m, 4H) ppm.

IV-3:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(6-(4-methylpiperazin-1-yl)pyridazin-3-yl)-5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 9.10 (s, NH), 8.39 (s, NH), 8.26 (d, NH), 8.21(s, 1H), 7.95 (t, J=13.8, 1H), 7.73 (s, 1H), 7.47-7.25 (m, 2H), 7.18 (d,J=10.4, 1H), 3.20-3.60 (m, 8H), 2.26 (s, 3H), 2.18 (s, 3H).

IV-4:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(1H-indazol-6-yl)-5-methylpyrimidine-2,4-diamine

MS (m/e): 374.17 (M+H); ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.29 (s,1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.47 (d, J=9.0, 1H), 7.42(s, 1H), 7.19 (d, J=8.4, 2H), 7.09 (d, J=8.7, 1H), 2.11 (s, 3H); LCMS:purity: 94.20%.

IV-5:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(1,2-benzisoxazol-6-yl)-5-methylpyrimidine-2,4-diamine

LCMS: purity: 88.71%; MS (m/e): 375.25 (M+H); ¹H NMR (300 MHz, DMSO) δ11.64 (s, 1H), 10.80 (s, 1H), 9.74 (br, 1H), 7.91 (s, 1H), 7.28 (m, 7H),2.13 (s, 3H).

IV-6:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(1H-indazol-5-yl)-5-methylpyrimidine-2,4-diamine

LCMS: purity: 99.84%; MS (m/e): 374.21 (M+H); ¹H NMR (300 MHz, DMSO) δ11.24 (br, 1H), 8.93 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H),7.65 (s, 1H), 7.43 (d, J=9.0, 1H), 7.30 (m, 3H), 7.22 (d, J=8.7, 1H),2.09 (s, 3H).

IV-7:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-[2-(piperazino)pyridin-4-yl]-5-methylpyrimidine-2,4-diamine

LCMS: purity: 96.84%; MS (m/e): 419.34 (M+H); ¹H NMR (300 MHz, DMSO) δ11.98 (br, 1H), 11.70 (br, 1H), 7.83 (s, 1H), 7.60 (t, J=5.7, 1H), 7.43(m, 2H), 7.27 (m, 2H), 6.28 (d, 1H), 5.97 (s, 1H), 3.74 (br, 4H), 2.11(s, 3H).

IV-8:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-[2-(4-methylpiperazino)pyridin-4-yl]-5-methylpyrimidine-2,4-diamine

LCMS: purity: 94.61%; MS (m/e): 433.34 (M+H); ¹H NMR (300 MHz, DMSO) δ12.25 (br, 1H), 11.74 (s, 1H), 9.42 (s, 1H), 8.32 (s, 1H), 7.68 (d, 1H),7.55 (br, 1H), 7.31-7.25 (m, 3H), 6.31 (d, 1H), 6.00 (s, 1H), 4.32 (d,2H), 3.90 (t, 4H), 3.39 (s, 3H), 2.26 (s, 3H).

IV-9:N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methyl-1,2-benzisoxazol-5-yl)-5-methylpyrimidine-2,4-diamine

LCMS: purity: 100%; MS (m/e): 389.26 (M+H); ¹H NMR (300 MHz, DMSO) δ11.48 (br, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H),7.70 (d, J=8.7, 1H), 7.49 (d, J=8.7, 1H), 7.34 (d, 2H), 7.21 (d, J=9.0,1H), 2.21 (s, 3H), 2.10 (s, 3H).

IV-10:(Z)-2-Methyl-9-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-3,6-dihydro-2H-benzo[c]azocin-1-one

¹H NMR (DMSO-d₆) δ: 11.55 (br. s., 1H), 9.08 (s, 1H), 8.35 (s, 1H), 8.11(s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.54 (d, J=6.6 Hz, 1H), 7.23-7.33(m, 1H), 7.17 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 5.92 (d, J=5.2Hz, 1H), 5.64 (br. s., 1H), 2.84-3.02 (m, 4H), 2.08 (m, 6H) ppm; MS (ES)443 (M+H);

IV-11:5-[2-(2,2-Difluoro-benzo[1,3]dioxol-4-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.70 (s, 1H), 10.24 (br. s., 1H), 9.65 (br.s., 1H), 7.90 (s, 1H), 7.02-7.33 (m, 6H), 2.14 (s, 3H) ppm; MS (ES) 414(M+H).

IV-12:5-[2-(9-Isopropylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.83 (s, 1H), 10.62 (br. s., 1H), 9.75 (br.s., 1H), 8.86 (br. s., 1H), 7.93 (s, 1H), 7.43 (d, J=8.0 Hz, 1H),7.26-7.33 (m, 1H), 7.22 (s, 1H), 7.15 (br. s., 1H), 7.07 (d, J=8.3 Hz,1H), 4.25 (br. s., 1H), 3.27 (br. s., 1H), 2.83 (br. s., 2H), 2.43-2.53(m, 2H), 2.13 (s, 3H), 1.95 (d, J=9.4 Hz, 2H), 1.57-1.77 (m, 2H), 1.20(d, J=6.3 Hz, 3H), 1.16 (d, J=6.3 Hz, 3H) ppm; MS (ES) 459 (M+H).

IV-13:5-{2-[9-(3-Diethylamino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 10.70 (s, 1H), 10.16 (s, 1H), 9.82 (s, 1H),7.93 (s, 1H), 7.67 (d, 1H), 7.33 (s, 1H), 7.18-6.79 (m, 3H), 4.15-3.77(m, 4H), 3.82-3.52 (m, 1H), 3.57-3.31 (m, 4H), 2.70-2.43 (m, 2H),2.45-2.27 (m, 1H), 2.11 (s, 3H), 1.94-1.57 (m, 2H), 1.19 (s, 6H) ppm; MS(ES) 542 (M+H).

IV-14:2-Methyl-9-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-3,4,5,6-tetrahydro-2H-benzo[c]azocin-1-one

¹H NMR (DMSO, 300 MHz): δ 11.75-11.32 (m, 1H), 9.03 (s, 1H), 8.32 (s,1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.57 (d, J=9.7, 2H), 7.30 (d, J=3.9,1H), 7.17 (d, J=8.5, 1H), 6.95 (d, J=8.3, 1H), 3.25-2.99 (m, 2H), 2.95(s, 3H), 2.77-2.55 (m, 2H), 2.42-2.21 (m, 2H), 2.07 (s, 3H), 1.85-1.47(m, 2H), 1.49-1.12 (m, 2H) ppm; MS (ES) 445 (M+H).

IV-15:6-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-3,4-dihydro-2H-isoquinolin-1-one

¹H NMR (DMSO, 300 MHz): δ 11.71 (s, 1H), 10.49 (s, 1H), 9.79 (s, 1H),7.93 (d, J=21.2, 1H), 7.72 (s, 1H), 7.54 (s, 1H), 7.23 (d, J=6.2, 1H),7.14 (s, 1H), 2.82 (s, 1H), 2.48 (s, 1H), 2.14 (s, 2H), 1.01 (d, J=6.1,1H) ppm; MS (ES) 403 (M+H).

IV-16:5-[2-(2,2-Dioxo-1H-benzo[e][1,3,4]oxathiazin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.96-11.53 (m, 1H), 10.61-10.24 (m, 1H),9.99-9.56 (m, 1H), 7.87 (s, 1H), 7.46-7.12 (m, 2H), 7.11-6.86 (m, 1H),6.71 (s, 1H), 5.04 (s, 2H), 2.12 (s, 3H) ppm; MS (ES) 441 (M+H).

IV-17:5-[2-(2,2-Dimethyl-benzo[1,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.74 (s, 1H), 10.37 (s, 1H), 9.91 (s, 1H),7.83 (s, 1H), 7.28 (d, J=8.5, 1H), 7.19 (s, 1H), 7.11 (d, J=10.2, 1H),6.95 (s, 1H), 6.70 (d, J=8.5, 1H), 6.59 (d, J=10.3, 1H), 2.12 (s, 3H),1.57 (s, 6H) ppm; MS (ES) 406 (M+H).

IV-18:(Z)-5-(5-methyl-2-(1-oxo-2,3-dihydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₂H₁₈N₆O₃. MS (ESI) m/z 415.09 (M+1)⁺.

IV-19:(Z)-5-(5-methyl-2-(2-methyl-1-oxo-2,3-dihydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₀N₆O₃. MS (ESI) m/z 429.11 (M+1)⁺.

IV-20:(Z)-5-(5-methyl-2-(2-methyl-1-oxo-2,3-dihydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₀N₆O₃. MS (ESI) m/z 429.11 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.71(s, 1H, NH), 10.28 (s, 1H, NH), 9.95 (s, 1H, NH), 7.93 (s, 1H, ArH),7.67 (d, J=13.0, 1H, ArH), 7.44 (s, 1H, ArH), 7.32 (m, 2H, ArH),7.23-7.10 (m, 2H, ArH), 6.27 (m, 2H, 2CH), 3.55 (d, J=5.9, 2H, CH₂),3.02 (s, 3H, CH₃), 2.14 (s, 3H, CH₃).

IV-21:5-(5-methyl-2-(2-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₃H₂₂N₆O₃. MS (ESI) m/z 431.12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.65(s, 1H, NH), 9.25 (s, 1H, NH), 8.12 (s, 1H, NH), 7.89 (s, 1H, ArH), 7.54(m, 1H, ArH), 7.48-7.32 (m, 2H, ArH), 7.25-7.19 (m, 2H, ArH), 7.04 (d,J=8.7, 1H, ArH), 3.09 (t, J=5.8, 2H, CH₂), 2.98 (s, 3H, CH₃), 2.34 (t,J=6.3, 2H, CH₂), 2.08 (s, 3H, CH₃), 1.90-1.76 (m, 2H, CH₂).

IV-22:5,5′-(5-methylpyrimidine-2,4-diyl)bis(azanediyl)dibenzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 11.62 (s, 1H), 9.94 (s, 1H),9.41 (s, 1H), 7.86 (s, 1H), 7.32 (br s, 3H), 7.25-7.15 (m, 3H), 2.19 (s,3H); LRMS (M+) m/z 390.97.

IV-23:5-(5-methyl-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.02 (br s, 1H), 9.59 (br s,1H), 9.49 (s, 1H), 7.88 (s, 1H), 7.29-7.24 (m, 4H), 7.11 (d, J=8.0, 1H),6.98 (s, 1H), 2.66 (br t, J=6.2, 2H), 2.19 (s, 3H), 2.16-2.09 (m, 4H);LRMS (M+) m/z 417.06.

IV-24:5-(5-methyl-2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.13 (s, 1H), 10.09 (s, 1H),9.59 (s, 1H), 7.86 (s, 1H), 7.34-7.27 (m, 3H), 7.10 (d, J=8.0, 1H), 7.04(d, J=8.0, 1H), 6.77 (s, 1H), 2.85 (t, J=7.4, 2H), 2.46 (t, J=7.4, 2H),2.19 (s, 3H); LRMS (M+) m/z 403.00.

IV-25:6-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one

¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.76 (s, 1H), 10.05 (s, 1H),9.59 (s, 1H), 7.84 (s, 1H), 7.30-7.28 (m, 3H), 7.07 (dd, J=8.6, 2.2,1H), 6.87 (d, J=8.6, 1H), 6.83 (br s, 1H), 4.58 (s, 2H), 2.18 (s, 3H);LRMS (M+) m/z 405.00.

IV-26:5-(2-(3,3-dimethyl-2-oxoindolin-6-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.83 (s, 1H), 10.37 (s, 1H), 10.11 (s, 1H),9.70 (s, 1H), 7.84 (s, 1H), 7.32 (d, J=8.4, 1H), 7.27-7.25 (m, 3H), 7.21(dd, J=8.2, 2.0, 1H), 6.79 (d, J=8.2, 1H), 2.18 (s, 3H), 1.12 (s, 6H);LRMS (M+) m/z 417.05.

IV-27:5-(5-methyl-2-(1-methyl-2-oxoindolin-5-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.80 (s, 1H), 10.29 (s, 1H), 9.78 (s, 1H),7.87 (s, 1H), 7.40-7.37 (m, 2H), 7.27-7.24 (m, 3H), 6.93 (d, J=8.2, 1H),3.43 (s, 2H), 3.13 (s, 3H), 2.19 (s, 3H); LRMS (M+) m/z 403.98.

IV-28:5-(5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.92 (s, 1H), 10.13 (s, 1H),9.63 (s, 1H), 7.80 (s, 1H), 7.32-7.28 (m, 3H), 7.06-7.01 (m, 3H), 3.31(s, 3H), 2.18 (s, 3H); LRMS (M+) m/z 404.00.

IV-29:5-(5-methyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 10.68 (s, 2H), 10.14 (s, 1H),9.66 (s, 1H), 7.79 (s, 1H), 7.31-7.29 (m, 3H), 6.99 (d, J=8.1, 1H), 6.94(s, 1H), 6.87 (d, J=8.1, 1H), 2.18 (s, 3H); LRMS (M+) m/z 389.96.

IV-30:5-(5-methyl-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 10.16 (s, 1H), 9.73 (s, 1H),7.92 (s, 1H), 7.49 (s, 1H), 7.30-7.23 (m, 3H), 7.17 (br s, 2H), 2.96 (s,3H), 2.60 (t, J=6.5, 2H), 2.19 (s, 3H), 2.17-2.12 (m, 2H), 2.09-2.02 (m,2H); LRMS (M+) m/z 431.08.

IV-31:5-(5-methyl-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 9.20 (s, 1H), 8.93 (s, 1H), 8.32(s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.38 (d, J=8.6, 1H), 7.29 (d,J=8.6, 2H), 7.21 (d, J=8.6, 1H), 6.71 (d, J=8.6, 1H), 2.40 (t, J=7.1,2H), 2.11-1.90 (m, 7H).

IV-32:7-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 10.63 (s, 1H), 10.25 (s, 1H),9.75 (s, 1H), 7.85 (s, 1H), 7.29 (d, J=8.5, 1H), 7.21 (s, 1H), 7.14 (d,J=8.5, 1H), 7.11 (s, 1H), 6.85 (d, J=8.5, 1H), 6.73 (d, J=8.5, 1H), 4.42(s, 2H), 2.12 (s, 3H).

IV-33:5-(5-methyl-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.08 (s, 1H), 10.09 (s, 1H),9.66 (s, 1H), 7.82 (s, 1H), 7.29 (d, J=9.0, 1H), 7.22 (app s, 2H), 7.21(d, J=8.5, 1H), 7.10 (d, J=8.5, 1H), 6.72 (d, J=8.5, 1H), 2.60 (t,J=7.4, 2H), 2.35 (t, J=7.4, 2H), 2.12 (s, 3H).

IV-34:5-(5-methyl-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

¹H NMR (300 MHz, DMSO) δ 11.79 (s, 1H), 10.39 (s, 1H), 9.78 (s, 1H),7.90 (s, 1H), 7.34-7.15 (m, 6H), 3.14 (s, 3H), 2.31 (t, J=6.6, 2H), 2.13(s, 3H), 2.04 (t, J=6.6, 2H), 1.86 (t, J=6.6, 2H).

IV-35:5-methyl-N2-(3,4-methylenedioxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.58 (br, 1H), 8.84 (s, 1H), 8.30 (s, 1H),7.81 (s, 1H), 7.36 (s, 1H), 7.25 (s, 2H), 7.17 (d, J=9.6, 1H), 6.95 (d,J=8.7, 1H), 6.67 (d, J=8.4, 1H), 5.86 (s, 2H), 2.07 (s, 3H); LCMS:purity: 87.13%; MS (m/e): 378.23 (M+H).

IV-36:N2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.21 (s, 1H), 8.40 (s, 1H), 7.85 (s, 2H), 7.20(s, 2H), 7.17 (s, 2H), 7.14 (m, 1H), 2.08 (s, 3H); ¹⁹F NMR (282 MHz,DMSO) δ −65.40; LCMS: purity: 95.27%; MS (m/e): 414.22 (M+H).

IV-37:N2-(3,4-ethylenedioxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 8.75 (s, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 7.28(t, J=2.4, 2H), 7.24 (d, J=8.1, 1H), 7.18 (d, J=8.4, 1H), 6.92 (d,J=8.7, 1H), 6.59 (d, J=9.0, 1H), 4.11 (s, 4H), 2.07 (s, 3H); LCMS:purity: 89.62%; MS (m/e): 392.25 (M+H).

IV-38:N2-(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.50 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 7.79(s, 1H), 7.27 (m, 2H), 7.20 (s, 2H), 6.80 (dd, J=2.1, 8.4, 1H), 6.56 (d,J=8.4, 1H), 2.07 (s, 3H), 1.56 (s, 6H); LCMS: purity: 96.72%; MS (m/e):406.26 (M+H).

IV-39:N2-[spiro(2,1′-cyclohexan)-1,3-benzodioxol-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.51 (s, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.80(s, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 7.25 (d, J=8.1, 1H), 7.18 (d,J=7.5, 1H), 6.82 (d, J=9.0, 1H), 6.57 (d, J=9.0, 1H), 2.06 (s, 3H), 1.80(t, 4H), 1.62 (t, 4H), 1.43 (t, 2H); LCMS: purity: 90.25%; MS (m/e):446.22 (M+H).

IV-40:N2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.16 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.37(s, 1H), 7.89 (s, 1H), 7.30 (s, 1H), 7.29 (d, J=7.5, 1H), 7.17 (d,J=7.8, 1H), 3.89 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H); LCMS: purity:94.01%; MS (m/e): 403.23 (M+H).

IV-41:5-methyl-N2-(1-methylindazol-6-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.87 (br, 1H), 9.20 (s, 1H), 8.37 (s, 1H),8.06 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=8.7, 1H), 7.36 (s,1H), 7.34 (d, J=10.8, 1H), 7.21 (d, J=8.4, 2H), 3.57 (s, 3H), 2.12 (s,3H); LCMS: purity: 96.12%; MS (m/e): 388.24 (M+H).

IV-42:5-methyl-N2-(1-methylindazol-5-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.08(s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.43 (d, J=3.3, 2H), 7.33 (d,J=8.4, 1H), 7.29 (s, 1H), 7.23 (d, J=8.4, 1H), 3.96 (s, 3H), 2.10 (s,3H); LCMS: purity: 93.96%; MS (m/e): 388.25 (M+H).

IV-43:5-methyl-N2-(3-methylisoxazolo[5,4-b]pyridin-5-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 10.06 (br, 1H), 9.27 (br, 1H),8.59 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.21 (s, 3H), 2.28 (s, 3H),2.14 (s, 3H); LCMS: purity: 93.10%; MS (m/e): 390.17 (M+H).

IV-44:N2-[4-(2-methoxyethyl)-2H-1,4-benzoxazin-3(4H)-one-7-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 9.91 (br, 1H), 7.84 (s, 1H),7.30 (d, J=8.7, 1H), 7.22 (s, 1H), 7.17 (s, 2H), 7.12 (d, J=9.3, 1H),6.98 (d, J=9.0, 1H), 4.50 (s, 2H), 4.01 (t, 2H), 3.47 (t, J=5.4, 2H),3.20 (s, 3H), 2.13 (s, 3H); LCMS: purity: 93.04%; MS (m/e): 463.24(M+H).

IV-45:N2-[2,2-dimethyl-4-(2-methoxyethyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-7-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.64(s, 1H), 7.28 (d, J=8.7, 1H), 7.19 (s, 2H), 4.13 (t, 2H), 3.48 (t, 2H),3.20 (s, 3H), 2.13 (s, 3H), 1.34 (s, 6H); LCMS: purity: 86.59%; MS(m/e): 492.25 (M+H).

IV-46:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-7-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 11.15 (s, 1H), 9.81 (br, 1H),9.38 (br, 1H), 7.85 (s, 2H), 7.55 (s, 1H), 7.27 (d, J=8.7, 1H), 7.21 (s,1H), 7.18 (d, 1H), 4.51 (s, 2H), 2.12 (s, 3H); LCMS: purity: 92.36%; MS(m/e): 406.18 (M+H).

IV-47:5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-6-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 7.89(s, 1H), 7.64 (d, J=9.3, 1H), 7.41 (d, 2H), 7.21 (d, J=8.7, 1H), 7.18(d, J=10.5, 1H), 6.54 (s, 1H), 4.53 (s, 2H), 2.09 (s, 3H); LCMS: purity:85.46%; MS (m/e): 406.19 (M+H).

IV-48:5-methyl-N2-(3-methylindazol-6-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 12.18 (s, 1H), 11.54 (s, 1H), 9.08 (s, 1H),8.30 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.42 (d, J=8.7, 3H), 7.21 (d,J=9.0, 2H), 2.38 (s, 3H), 2.10 (s, 3H); LCMS: purity: 95.21%; MS (m/e):388.19 (M+H).

IV-49:5-methyl-N2-(3-methylindazol-5-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 12.38 (s, 1H), 11.56 (s, 1H), 9.02 (s, 1H),8.45 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.41 (d, 1H), 7.35 (d, 2H),7.28 (d, 1H), 7.18 (d, 1H), 2.15 (s, 3H), 2.08 (s, 3H); LCMS: purity:98.29%; MS (m/e): 388.20 (M+H).

IV-50:N2-[2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one-7-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 90.73%; MS (m/e): 433.12 (M+H).

IV-51:5-(5-methyl-2-(6-methylpyridin-2-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneIV-52:5-(5-methyl-2-(5-methylpyridin-2-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-oneIV-53:5-[2-(Isoquinolin-6-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 12.01 (s, 1H), 9.70 (s, 2H), 9.37-9.04 (m,1H), 8.71 (s, 2H), 8.42-7.85 (m, 2H), 7.69 (s, 1H), 7.53 (s, 1H),7.44-7.05 (m, 1H), 6.84 (s, 1H), 2.22 (s, 3H) ppm; MS (ES) 385 (M+H);

IV-54:5-[5-Methyl-2-(naphthalen-2-ylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.85 (s, 1H), 10.94 (s, 1H), 10.06 (s, 1H),7.94 (d, J=14.9, 2H), 7.80 (d, J=8.7, 1H), 7.39 (dd, J=8.5, 17.9, 3H),7.30-7.03 (m, 2H), 2.16 (s, 3H) ppm; MS (ES) 384 (M+H);

IV-55:5-[2-(4-Methoxy-naphthalen-2-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.15 (s, 1H), 8.42 (s, 1H), 7.93 (t, J=9.5,2H), 7.42-7.25 (m, 3H), 7.25-7.10 (m, 2H), 3.81 (s, 3H), 2.11 (s, 3H)ppm; MS (ES) 414 (M+H);

IV-56:5-[2-(4-Hydroxy-naphthalen-2-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 8.48 (s, 1H), 8.18-8.08 (m, 1H), 8.09-8.01 (m,1H), 7.90-7.79 (m, 1H), 7.71 (s, 1H), 7.46-7.35 (m, 2H), 7.24 (m, 3H),6.82 (d, J=8.0, 1H), 6.72 (d, J=8.4, 1H), 2.01 (s, 3H) ppm; MS (ES) 400(M+H);

IV-57:5-[2-(Isoquinolin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 12.08 (s, 1H), 9.64 (s, 2H), 9.12 (m, 1H),8.78 (s, 2H), 8.40-7.79 (m, 2H), 7.61 (s, 1H), 7.48 (s, 1H), 7.34 (m,1H), 6.79 (s, 1H), 2.13 (s, 3H) ppm; MS (ES) 385 (M+H);

IV-58:N2-(4-methoxypyridin-2-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.27 (s, 1H), 8.93 (s, 1H), 8.38(d, J=8.1, 1H), 8.29 (s, 1H), 7.31 (s, 1H), 7.27 (m, 2H), 6.67 (d, 1H),6.41 (s, 1H), 3.92 (s, 3H), 2.27 (s, 3H); LCMS: purity: 83.21%; MS(m/e): 365.36 (MH+).

IV-59:5-[5-Methyl-2-(2,4,6-trifluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.54 (s, 1H), 8.69-8.49 (m, 1H), 8.40 (s,1H), 7.76 (s, 1H), 7.36-7.14 (m, 4H), 7.05 (d, J=8.5, 1H), 2.04 (s, 3H)ppm; MS (ES) 388 (M+H);

IV-60:5-(2-(2,6-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₂₀H₁₉N₅O₂. MS (ESI) m/z 362.21 (M+1)⁺.

IV-61:5-[5-Methyl-2-(2,4,6-trimethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.63-11.41 (m, 1H), 9.46-9.27 (m, 1H),8.48-8.34 (m, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.75-7.53 (m, 1H), 6.87(d, J=9.7, 1H), 6.58 (s, 2H), 2.21 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H),2.03 (s, 3H) ppm; MS (ES) 376 (M+H);

IV-62:5-(2-(2-fluoro-6-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one

C₁₉H₁₆FN₅O₂. MS (ESI) m/z 366.23 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.19(s, 1H, NH), 8.15 (s, 1H, NH), 8.10 (s, 1H, NH), 7.72 (s, 1H, ArH),7.36-7.33 (m, 1H, ArH), 7.23 (s, 1H, ArH), 7.10-7.03 (m, 3H, ArH),6.96-6.93 (m, 1H, ArH), 2.15 (s, 3H, CH₃), 2.02 (s, 3H, CH₃).

IV-63:N2-(3-fluoropyridin-4-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 9.06 (d, 2H), 8.87 (d, J=8.1, 1H), 8.19 (s,1H), 7.10 (s, 1H), 7.01 (m, 3H), 2.22 (s, 3H); LCMS: purity: 96.38%; MS(m/e): 353.36 (MH+).

IV-64:N2-(3-fluoropyridin-4-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediaminetrifluoroacetic acid salt

¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 9.24-9.16 (m, 3H), 8.99 (s, 1H),8.94 (d, J=7.5, 1H), 8.28 (s, 1H), 7.37 (s, 1H), 7.32 (s, 2H), 7.13 (t,J=7.5, 1H), 2.25 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −161.09; LCMS:purity: 87.83%; MS (m/e): 353.35 (MH+).

Example 2 Assay for CD23 Expression on Ramos B-Cells Stimulated by IL-4

B-cells stimulated with cytokine Interleukin-4 (IL-4) activate theJAK/Stat pathway through phosphorylation of the JAK family kinases,JAK-1 and JAK-3, which in turn phosphorylate and activate thetranscription factor Stat-6. One of the genes upregulated by activatedStat-6 is the low affinity IgE receptor, CD23. To study the effect ofinhibitors on the JAK family kinases, human Ramos B cells werestimulated with human IL-4 and the surface expression of CD23 wasmeasured.

The Ramos B-cell line was acquired from ATCC (ATCC Catalog No.CRL-1596). The cells were cultured in RPMI 1640 (Cellgro, MediaTech,Inc., Herndon, Va., Cat No. 10-040-CM) with 10% FBS, heat inactivated(JRH Biosciences, Inc, Lenexa, Kans., Cat No. 12106-500M) according toATCC propagation protocol. Cells were maintained at a density of3.5×10⁵. The day before the experiment, Ramos B-cells were diluted to3.5×10⁵ cells/mL to ensure that they were in a logarithmic growth phase.

Cells were spun down and suspended in RPMI with 5% serum. 5×10⁴ cellswere used per point in a 96-well tissue culture plate. Cells werepre-incubated with compound or DMSO (Sigma-Aldrich, St. Louis, Mo., CatNo. D2650) vehicle control for 1 hour in a 37° C. incubator. Cells werethen stimulated with IL-4 (Peprotech Inc., Rocky Hill, N.J., Cat No.200-04) for a final concentration of 50 units/mL for 20-24 hours. Cellswere then spun down and stained with anti-CD23-PE (BD Pharmingen, SanDiego, Calif., Cat No. 555711) and analyzed by FACS. Detection wasperformed using a BD LSR I System Flow Cytometer, purchased from BectonDickinson Biosciences of San Jose, Calif. The IC₅₀ calculated based onthe results of this assay are provided in Table IX.

Example 3 Assay for Human Primary T-cell Proliferation Stimulated byIL-2

Primary human T-cells derived from peripheral blood and pre-activatedthrough stimulation of the T-cell receptor and CD28, proliferate invitro in response to the cytokine Interleukin-2 (IL-2). Thisproliferative response is dependent on the activation of JAK-1 and JAK-3tyrosine kinases, which phosphorylate and activate the transcriptionfactor Stat-5.

Human primary T cells were prepared as follows. Whole blood was obtainedfrom a healthy volunteer, mixed 1:1 with PBS, layered on to FicollHypaque (Amersham Pharmacia Biotech, Piscataway, N.J., Catalog#17-1440-03) in 2:1 blood/PBS:ficoll ratio and centrifuged for 30 min at4° C. at 1750 rpm. The lymphocytes at the serum: ficoll interface wererecovered and washed twice with 5 volumes of PBS. The cells wereresuspended in Yssel's medium (Gemini Bio-products, Woodland, Calif.,Catalog #400-103) containing 40 U/mL recombinant IL2 (R and D Systems,Minneapolis, Minn., Catalog #202-IL (20 μg)) and seeded into a flaskpre-coated with 1 μg/mL anti-CD3 (BD Pharmingen, San Diego, Calif.,Catalog #555336) and 5 μg/mL anti-CD28 (Immunotech, Beckman Coulter ofBrea Calif., Catalog #IM1376). The primary T-cells were stimulated for3-4 days, then transferred to a fresh flask and maintained in RPMI with10% FBS and 40 U/mL IL-2.

The day prior to the assay set up, primary T-cells were centrifuged andresuspended in fresh RPMI with 10% FBS but without IL-2 and starvedovernight. For the assay, the primary T-cells were centrifuged andresuspended Yssel's medium at 2×10⁶ cells/mL. 50 μL of cell suspensioncontaining 80 U/mL IL-2 was added to each well of a flat bottom 96 wellblack plate. For the unstimulated control, IL-2 was omitted from thelast column on the plate. Compounds were serially diluted in dimethylsulfoxide (DMSO, 99.7% pure, cell culture tested, Sigma-Aldrich, St.Louis, Mo., Catalog No. D2650) from 5 mM in 3-fold dilutions, and thendiluted 1:250 in Yssel's medium. 50 μL of 2× compound was added per wellin duplicate and the cells were allowed to proliferate for 72 hours at37° C.

Proliferation was measured using CellTiter-Glo® Luminescent CellViability Assay (Promega), which determines the number of viable cellsin culture based on quantitation of the ATP present, as an indicator ofmetabolically active cells. The substrate was thawed and allowed to cometo ambient temperature. After mixing the Cell Titer-Glo reagent anddiluent together, 100 μL was added to each well. The plates were mixedon an orbital shaker for two minutes to induce lysis and incubated atambient temperature for an additional ten minutes to allow the signal toequilibrate. Detection was performed using a Wallac Victor2 1420multilabel counter purchased from Perkin Elmer, Shelton, Conn.

Example 4 Assay for ICAM1 Expression on A549 Epithelial Cells Stimulatedby IFNγ

Lung epithelial cells, A549, up-regulate ICAM-1 (CD54) surfaceexpression in response to a variety of different stimuli. Therefore,using ICAM-1 expression as readout, compound effects on differentsignaling pathways can be assessed in the same cell type. IFNγup-regulates ICAM-1 through activation of the JAK/Stat pathway. In thisexample, the up-regulation of ICAM-1 by IFNγ was assessed.

The A549 lung epithelial carcinoma cell line originated from theAmerican Type Culture Collection. Routine culturing was with F12K media(Mediatech Inc., Lenexa, Kans., Cat. No. 10-025-CV) with 10% fetalbovine serum, 100 I.U. penicillin and 100 ng/mL streptomycin (completeF12k media). Cells were incubated in a humidified atmosphere of 5% CO₂at 37° C. Prior to use in the assay, A549 cells were washed with PBS andtrypsinized (Mediatech Inc., Cat. No. 25-052-CI) to lift the cells. Thetrypsin cell suspension was neutralized with complete F12K media andcentrifuged to pellet the cells. The cell pellet was resuspended incomplete F12K media at a concentration of 2.0×10⁵/mL. Cells were seededat 20,000 per well, 100 μL total volume, in a flat bottom tissue cultureplate and allowed to adhere overnight.

On day two, A549 cells were pre-incubated with test compound or DMSO(control) (Sigma-Aldrich, St. Louis, Mo., Catalog No. D2650) for 1 hour.The cells were then stimulated with IFNγ (75 ng/mL) (Peprotech Inc.,Rocky Hill, N.J., Cat. No. 300-02) and allowed to incubate for 24 hours.The final test compound dose range was 30 μM to 14 nM in 200 μL F12Kmedia containing 5% FBS, 0.3% DMSO.

On day three, the cell media was removed and the cells were washed with200 μL PBS (phosphate buffered saline). Each well was trypsinized todissociate the cells, then neutralized by addition of 200 μL completeF12K media. Cells were pelleted and stained with an APC conjugated mouseanti-human ICAM-1 (CD54) (BD Pharmingen, San Diego, Calif., Catalog#559771) antibody for 20 minutes at 4° C. Cells were washed with icecold FACS buffer (PBS+2% FBS) and surface ICAM-1 expression was analyzedby flow cytometry. Detection was performed using a BD LSR I System FlowCytometer, purchased from BD Biosciences of San Jose, Calif. Events weregated for live scatter and the geometric mean was calculated(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Geometric means were plotted against the compound concentration togenerate a dose response curve.

Example 5 Assay for ICAM1 Expression on U937 Myeloid Cells Stimulated byIFNγ

Human U937 monocytic cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The U937 human monocytic cell line was obtained from ATCC of RockvilleMd., catalog number CRL-1593.2, and cultured in RPM1-1640 mediumcontaining 10% (v/v) FCS. U937 cells were grown in 10% RPMI. The cellswere then plated at a concentration of 100,000 cells per 160 μL in 96well flat bottom plates. The test compounds were then diluted asfollows: 10 mM test compound was diluted 1:5 in DMSO (3 μL 10 mM testcompound in 12 μL DMSO), followed by a 1:3 serial dilution of testcompound in DMSO (6 μL test compound serially diluted into 12 μL DMSO togive 3-fold dilutions). Then 4 μL of test compound was transferred to 76μL of 10% RPMI resulting in a 10× solution (100 μM test compound, 5%DMSO). For control wells, 4 μL of DMSO was diluted into 76 μL 10% RPMI.The assay was performed in duplicate with 8 points (8 3-fold dilutionconcentrations from 10 μM) and with 4 wells of DMSO only (control wells)under stimulated conditions and 4 wells of DMSO only under unstimulatedconditions.

The diluted compound plate was mixed 2× using a multimek (BeckmanCoulter of Brea, Calif.) and then 20 μL of the diluted compounds wastransferred to the 96 well plate containing 160 μL of cells, which werethen mixed again twice at low speeds. The cells and compounds were thenpre-incubated for 30 minutes at 37° C. with 5% CO₂.

The 10× stimulation mix was made by preparing a 100 ng/mL solution ofhuman IFNγ in 10% RPMI. The cells and compound were then stimulated with20 μL of IFNγ stimulation mix to give a final concentration of 10 ng/mLIFNγ, 10 μM test compound, and 0.5% DMSO. The cells were kept underconditions for stimulation for 18-24 hours at 37° C. with 5% CO₂.

The cells were transferred to a 96 well round bottom plate for stainingand then kept on ice for the duration of the staining procedure. Cellswere spun down at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. Following removal of the supernatant, 1 μL APCconjugated mouse anti-human ICAM-1 antibody was added per 100 μL FACSbuffer. The cells were then incubated on ice in the dark for 30 minutes.Following incubation, 150 μL of FACS buffer was added and the cells werecentrifuged at 1000 rpm for minutes at 4° C., following which thesupernatant was removed. After removal of the supernatant, 200 μL ofFACS buffer was added and the cells were resuspended. After suspension,the cells were centrifuged at 1000 rpm for 5 min at 4° C. Supernatantwas then removed prior to resuspension of the cells in 150 μL FACSbuffer.

Detection was performed using a BD LSR I System Flow Cytometer,purchased from BD Biosciences of San Jose, Calif. The live cells weregated for live scatter and the geometric mean of ICAM-APC was measured(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Both % live cells and ICAM-1 expression was analyzed. The assays for thetest compounds were carried out in parallel with a control compound ofknown activity. The EC₅₀ for the control compound is typically 40-100nM.

Example 6 JAK1, JAK2 and JAK3 Fluorescence Polarization Kinase Assays

This assay can be utilized to determine the potency of a compounddescribed herein against certain JAK kinases and the selectivity of acompound described herein in inhibiting certain JAK kinase activity invitro.

Reagents and Buffers Tyrosine Kinase Kit Green (Invitrogen, Cat #P2837)Acetylated Bovine Gamma Globulin (BGG) (Invitrogen, Cat #P2255) ActiveJAK1 (Carna Biosciences) Active JAK2 (Carna Biosciences) Active JAK3(Carna Biosciences) TK2 Peptide (Biotin-EGPWLEEEEEAYGWMDF-CONH₂) (SynPepCustom Synthesis) Methods

Test compounds were serially diluted in DMSO starting from 500× thedesired final concentration and then diluted to 1% DMSO in kinase buffer(20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mLacetylated BGG). Test compound in 1% DMSO (0.2% DMSO final) was mixed1:5 with ATP and substrate in kinase buffer at ambient temperature.

The kinase reactions were performed in a final volume of 20 μLcontaining peptide substrate and ATP and started by addition of kinasein kinase buffer. The reactions were allowed to proceed at ambienttemperature. Final substrate, ATP and enzyme concentrations and reactiontimes for the different kinase assays are listed in Table VIII.

TABLE VIII Final Substrate, ATP, Enzyme Concentrations and ReactionTimes Enzyme Substrate ATP Amount per Concen- Concen- Assay EnzymeReaction Substrate tration tration Time JAK1  20 ng TK2 10 μM 5 μM 20min JAK2 0.3 ng TK2 10 μM 5 μM 20 min JAK3   2 ng TK2 10 μM 5 μM 20 min

The reactions were stopped by adding 20 μL of PTK quench mix containingEDTA/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptidetracer (0.5× final) diluted in FP Dilution Buffer according tomanufacturer's instructions (Invitrogen). The plates were incubated for30 minutes in the dark at ambient temperature and then read on aPolarion fluorescence polarization plate reader (Tecan).

Data were converted to amount of phosphopeptide present using acalibration curve generated by competition with the phosphopeptidecompetitor provided in the Tyrosine Kinase Assay Kit, Green(Invitrogen). For IC₅₀ determination, the compounds were tested ateleven concentrations in duplicate and curve-fitting was performed bynon-linear regression analysis using Matlab version 6.5 (MathWorks,Inc., Natick, Mass., USA).

Example 7 Constitutively-Active JAK2-Dependent Cell Proliferation Assays

A mutation in the JH2 pseudokinase domain of JAK2 (JAK2 V617F) has beendescribed in chronic myeloproliferative disorders as well as a subset ofacute myeloid leukemia (AML) cell lines. Mutation of the negativeregulatory JH2 domain dysregulates the kinase enabling it toconstitutively associate with the EPO receptor and become activated.UKE-1 cells, derived from an AML patient, express JAK2 V617F whichdrives their proliferation. The IL-3-dependent BaF3 myeloid cell linewas engineered to express JAK2 V617F allowing it to proliferate in anIL-3-independent manner. The effect of JAK inhibitors on theproliferation of these cell lines can be used to assess the cellularactivity of the compounds against JAK2.

Reagents and Buffers

Dimethyl Sulfoxide (DMSO) (Sigma-Aldrich, Cat No. D2650) (Control)

Iscove's DMEM, ATCC Catalog #30-2005

1 M HEPES, Cellgro Catalog #25-060-CI (100 mL)

100 mM Sodium Pyruvate, Cellgro Catalog #25-000-CI (100 mL)

Penicillin/Streptomycin, 10000 U/mL each, Cellgro Catalog #30-002-CI(100 mL)

RPMI 1640 (Cellgro, Cat No. 10-040-CM)

Fetal Bovine Serum (JRH, Cat No. 12106-500M)

Donor Equine Serum, Hyclone Catalog #SH30074.02 (100 mL)

50 μM hydrocortisone solution, Sigma Catalog #H6909-10 ml (10 mL)

Culture Conditions

BaF3 V617F cells were maintained and plated in RPMI with 10% FBS.Plating density for these cells was 1×10⁵ cells/mL.

UKE-1 were maintained and plated in Iscove's DMEM containing 10% FBS,10% equine serum, 1% penicillin/streptomycin and 1 uM hydrocortisone.Plating density for these cells was 0.4×10⁶ cells/mL

Methods

The cells were resuspended in a corresponding medium at a required celldensity (see above). 100μ of cell suspension was added to each well of aflat bottom 96 well white plate. The compound was serially diluted inDMSO from 5 mM in 3-fold dilutions, and then diluted 1:250 in the RPMI1640 medium containing 5% FBS and pen/strep. 100 μL of resulting 2×compound solution was added per well in duplicate and the cells wereallowed to proliferate for 72 hours at 37° C.

Proliferation was measured using Cell Titer-Glo. The substrate wasthawed and allowed to come to room temperature. After removal of top 100μL of medium from each well, 100 μL of the premixed Cell Titer-Gloreagent was added to each well. The plates were mixed on an orbitalshaker for three minutes to induce lysis and incubated at ambienttemperature for an additional five minutes to allow the signal toequilibrate. The Luminescence was read on the Wallac Plate Reader.

The results of the ability of the compounds described herein to inhibitJAK3 activity, when tested under conditions described in Example 3above, are shown in Table V below. The compound designations in Table Vare consistent with those of Tables I-IV above. In Table V the activityis indicated by the following ranges: “A” represents compounds having anIC₅₀<0.5 μM; “B” represents compounds having an IC₅₀≧0.5 μM and <5 μM;“C” represents compounds having an IC₅₀≧5 μM and <10 μM; and “D”represents compounds having activity ≧10 μM.

The results of the ability of the compounds described herein to inhibitJAK3 activity, when tested under conditions described in Example 3above, are shown in Table V below.

The compound designations in Table V are consistent with those of TablesI-IV above. In Table V the activity is indicated by the followingranges: “A” represents compounds having an IC₅₀<0.5 μM; “B” representscompounds having an IC₅₀≧0.5 μM and <5 μM; “C” represents compoundshaving an IC₅₀≧5 μM and <10 μM; and “D” represents compounds havingactivity ≧10 μM.

TABLE V I-1 B I-2 A I-3 A I-4 A I-5 B I-6 A I-7 A I-8 A I-9 A I-10 AI-11 A I-12 D I-13 B I-14 A I-15 A I-16 A I-17 A I-18 A I-19 A I-20 AI-21 A I-22 A I-23 D I-24 A I-25 A I-26 A I-27 A I-28 A I-29 D I-30 AI-31 A I-32 B I-33 A I-34 A I-35 D I-36 A I-37 A I-38 A I-39 A I-40 DI-41 B I-42 B I-43 B I-44 A I-45 A I-46 A I-47 A I-48 A I-49 A I-50 AI-51 B I-52 A I-53 A I-54 A I-55 A I-56 A I-57 A I-58 D I-59 A I-60 DI-61 A I-62 B I-63 A I-64 D I-65 A I-66 A I-67 A I-68 A I-69 A I-70 AI-71 A I-72 A I-73 A I-74 A I-75 A I-76 B I-77 B I-78 B I-79 B I-80 AI-81 A I-82 A I-83 A I-84 A I-85 B I-86 D I-87 A I-88 A I-89 A I-90 AI-91 B I-92 D I-93 A I-94 A I-95 A I-96 A I-97 D I-98 A I-99 A I-100 AI-101 A I-102 A I-103 D I-104 A I-105 D I-106 A I-107 B I-108 A I-109 AI-110 A I-111 A I-112 A I-113 A I-114 A I-115 A I-116 A I-117 A I-118 AI-119 A I-120 A I-121 B I-122 A I-123 A I-124 A I-125 A I-126 A I-127 AI-128 A I-129 A I-130 A I-131 A I-132 A I-133 A I-134 A I-135 A I-136 AI-137 A I-138 A I-139 A I-140 A I-141 A I-142 A I-143 I-144 A I-145 AI-146 B I-147 A I-148 A I-149 A I-150 A I-151 A I-152 B I-153 A I-154 AI-155 A I-156 A I-157 A I-158 A I-159 A I-160 A I-161 A I-162 D I-163 AI-164 A I-165 A I-166 A I-167 A I-168 B I-169 A I-170 D I-171 A I-172 AI-173 A I-174 A I-175 A I-176 B I-177 A I-178 A I-179 D I-180 A I-181 AI-182 A I-183 A I-184 A I-185 D I-186 A I-187 A I-188 A I-189 A I-190 AI-191 A I-192 A I-193 B I-194 A I-195 A I-196 A I-197 D I-198 A I-199 AI-200 A I-201 A I-202 A I-203 A I-204 A I-205 A I-206 A I-207 A I-208 AI-209 A I-210 A I-211 A I-212 A I-213 A I-214 A I-215 A I-216 A I-217 AI-218 A I-219 A I-220 A I-221 A I-222 B I-223 A I-224 B I-225 B I-226 BI-227 B I-228 A I-229 A I-230 B I-231 A I-232 A I-233 A I-234 A I-235 AI-236 A I-237 A I-238 A I-239 A I-240 A I-241 A I-242 A I-243 A I-244 AI-245 A I-246 A I-247 A I-248 A I-249 A I-250 A I-251 A I-252 A I-253 DI-254 A I-255 A I-256 A I-257 A I-258 A I-259 A I-260 A I-261 A I-262 AI-263 A I-264 A I-265 A I-266 A I-267 A I-268 A I-269 A I-270 A I-271 AI-272 A I-273 A I-274 A I-275 A I-276 A I-277 A I-278 A I-279 A I-280 AI-281 A I-282 A I-283 A I-284 A I-285 A I-286 A I-287 A I-288 A I-289 AI-290 A I-291 A I-292 A I-293 A I-294 A I-295 A I-296 A I-297 A I-298 AI-299 A I-300 A I-301 A I-302 A I-303 A I-304 A I-305 B I-306 A I-307 AI-308 A I-309 A I-310 A I-311 A I-312 A I-313 A I-314 A I-315 A I-316 AI-317 A I-318 A I-319 A I-320 A I-321 A I-322 A I-323 A I-324 A I-325 BI-326 A I-327 A I-328 B I-329 B I-330 C I-331 A I-332 A I-333 A I-334 AI-335 A I-336 A I-337 A I-338 A I-339 A I-340 A I-341 A I-342 A I-343 AI-344 A I-345 A I-346 A I-347 A I-348 A I-349 A I-350 A I-351 A I-352 AI-353 A I-354 A I-355 B I-356 C I-357 B I-358 B I-359 A I-360 A I-361 AI-362 A I-363 A I-364 A I-365 A I-366 A I-367 A I-368 A I-369 A I-370 AI-371 B I-372 A I-373 A I-374 A I-375 A I-376 A I-377 A I-378 A I-379 AI-380 A I-381 A I-382 A I-383 B I-384 A I-385 A I-386 A I-387 A I-388 AI-389 A I-390 A I-391 A I-392 A I-393 A I-394 A I-395 A I-396 A I-397 AI-398 A I-399 A I-400 A I-401 A I-402 A I-403 A I-404 A I-405 C I-406 BI-407 B I-408 A I-409 A I-410 A I-411 A I-412 A I-413 A I-414 A I-415 AI-416 A I-417 A I-418 A I-419 A I-420 A I-421 A I-422 A I-423 A I-424 AI-425 A I-426 A I-427 D I-428 A I-429 A I-430 A I-431 A I-432 A I-433 AI-434 A I-435 A I-436 A I-437 A I-438 A I-439 A I-440 A I-441 A I-442 AI-443 A I-444 A I-445 A I-446 A I-447 A I-448 A I-449 A I-450 D I-451 BI-452 A I-453 A I-454 A I-455 A I-456 A I-457 A I-458 A I-459 A I-460 AI-461 A I-462 A I-463 A I-464 A I-465 A I-466 A I-467 A I-468 A I-469 AI-470 A I-471 A I-472 A I-473 A I-474 A I-475 A I-476 D I-477 B I-478 AI-479 A I-480 D I-481 A I-482 A I-483 A I-484 B I-485 A I-486 A I-487 AI-488 A I-489 A I-490 A I-491 A I-492 A I-493 A I-494 B I-495 A I-496 AI-497 D I-498 B I-499 B I-500 B I-501 B I-502 B I-503 A I-504 A I-505 DI-506 A I-507 A I-508 A I-509 D I-510 A I-511 A I-512 A I-513 A I-514 AI-515 A I-516 A I-517 B I-518 A I-519 A I-520 B I-521 A I-522 A I-523 AI-524 D I-525 B I-526 B I-527 A I-528 B I-529 A I-530 A I-531 B I-532 AI-533 A I-534 I-535 A I-536 C I-537 A I-538 B II-1 A II-2 A II-3 A II-4A II-5 A II-6 D II-7 A II-8 A II-9 A II-10 A II-11 A II-12 A II-13 AII-14 A II-15 A II-16 A II-17 A II-18 A II-19 A II-20 A II-21 B II-22 AII-23 A II-24 B II-25 A II-26 A II-27 A II-28 A II-29 A II-30 A II-31 AII-32 A II-33 A II-34 A II-35 A II-36 A II-37 B II-38 A II-39 A II-40 AII-41 A II-42 B II-43 A II-44 A II-45 A II-46 B II-47 A II-48 A II-49 AII-50 A II-51 A II-52 A II-53 A II-54 A II-55 A II-56 A II-57 A II-58 AII-59 A II-60 A II-61 A II-62 A II-63 A II-64 A II-65 A II-66 B II-67 AII-68 A II-69 A II-70 A II-71 A II-72 A II-73 A II-74 A II-75 A II-76 AII-77 B II-78 A II-79 A II-80 A II-81 A II-82 A II-83 A II-84 A II-85 AII-86 A II-87 A II-88 A II-89 A II-90 A II-91 A II-92 A II-93 A II-94 AII-95 A II-96 A II-97 A II-98 A II-99 A II-100 A II-101 A II-102 AII-103 A II-104 A II-105 A II-106 A II-107 A II-108 A II-109 A II-110 AII-111 A II-112 A II-113 A II-114 A II-115 A II-116 A II-117 A II-118 AII-119 A II-120 A II-121 A II-122 A II-123 A II-124 A II-125 A II-126 BII-127 A II-128 A II-129 A II-130 A II-131 A II-132 A II-133 A II-134 AII-135 A II-136 A II-137 A II-138 A II-139 A II-140 A II-141 A II-142 AII-143 B II-144 A II-145 A II-146 A II-147 A II-148 B II-149 A II-150 AII-151 A II-152 D II-153 A III-1 A III-2 A III-3 A III-4 A III-5 A III-6A III-7 A III-8 A III-9 A III-10 A III-11 A III-12 A III-13 A III-14 AIV-1 A IV-2 A IV-3 D IV-4 A IV-5 A IV-6 A IV-7 C IV-8 D IV-9 A IV-10 AIV-11 A IV-12 A IV-13 B IV-14 A IV-15 A IV-16 A IV-17 A IV-18 A IV-19 AIV-20 A IV-21 A IV-22 A IV-23 A IV-24 A IV-25 A IV-26 A IV-27 A IV-28 AIV-29 A IV-30 A IV-31 A IV-32 A IV-33 A IV-34 A IV-35 A IV-36 A IV-37 AIV-38 A IV-39 A IV-40 A IV-41 A IV-42 A IV-43 A IV-44 A IV-45 A IV-46 AIV-47 D IV-48 A IV-49 A IV-50 A IV-51 B IV-52 B IV-53 C IV-54 A IV-55 AIV-56 C IV-57 D IV-58 D IV-59 D IV-60 C IV-61 D IV-62 B IV-63 C IV-64 B

Although the foregoing invention has been described in some detail tofacilitate understanding, the described embodiments are to be consideredillustrative and not limiting. It will be apparent to one of ordinaryskill in the art that certain changes and modifications can be practicedwithin the scope of the appended claims.

1. A compound, or pharmaceutically acceptable salt thereof, wherein thecompound isN2-(3,4,5-trimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine.